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Tedder, Thomas Fletcher

Overview:

Area of Study: Structure and function of B lymphocyte cell surface molecules that regulate B cell function, activation and signal transduction.

Overview: The focus of our laboratory is the identification, structural characterization, and functional analysis of cell surface molecules and signaling pathways that regulate B lymphocyte development and function. Cell surface molecules allow B cells to communicate with the extracellular environment by serving as transmembrane regulators, receptors for soluble factors, or by mediating cell–cell interactions. Our studies of B-cell–associated cell surface receptors, including CD19, CD20, CD21, CD22 and CD83, are aimed at determining how these molecules function, what their ligands are, how they generate transmembrane signals and regulate human and mouse B cell development, survival and activation. These studies lay the foundation for investigating mechanisms of immune dysregulation and the pathogenesis of immune disorders, such as autoimmunity, neoplastic transformation, and immunodeficiency syndromes in humans. We have expertise in cellular immunology, biochemistry, and molecular biology and are applying a wide range of techniques in understanding the regulatory pathways that govern normal and abnormal B cell function in mice and humans. Current studies are focused on identifying the molecular and cellular mechanisms by which B cells regulate T cell function and autoimmunity, with a particular emphasis on the regulatory B cell subset (B10 cells) that controls immune and inflammatory responses through their production IL-10, a potent negative regulatory cytokine. Current studies also focus on identifying the molecular and cellular mechanisms by which CD19, CD20 and CD22 mAb immunotherapies are effective for treating B cell malignancies and autoimmunity, with translational studies pursuing the development of molecular and cellular therapies for human disease.

We currently have open positions for Research Scientist appointments, students, and postdoctoral fellows.

Positions:

Alter Geller Professor for Research in Immunology in the School of Medicine

Immunology
School of Medicine

Professor of Immunology

Immunology
School of Medicine

Professor in the Department of Pediatrics

Pediatrics, Allergy and Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1984

Ph.D. — University of Alabama at Birmingham

Grants:

Research Training in Allergy and Clinical Immunology

Administered By
Pediatrics, Allergy and Immunology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2000
End Date
August 31, 2021

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 1975
End Date
June 30, 2021

Pathological B Cells: Novel Strategies to Prevent and Treat Chronic GVHD

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 15, 2015
End Date
June 30, 2020

Basic Immunology Training Program

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2002
End Date
June 30, 2019

Antigenome Technology for High Throughput Antibody Target Identification

Administered By
Immunology
AwardedBy
North Carolina Biotechnology Center
Role
Principal Investigator
Start Date
June 09, 2017
End Date
June 08, 2018

IDENTIFYING THE MICROBIAL AND SELF ANTIGENOMES OF NMOSD

Administered By
Immunology
AwardedBy
The Guthy-Jackson Charitable Foundation
Role
Principal Investigator
Start Date
November 01, 2015
End Date
January 31, 2018

Training Program in Inflammatory and Immunological Diseases

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
September 30, 1980
End Date
August 31, 2017

B10 cell development in systemic lupus erythematosus

Administered By
Immunology
AwardedBy
Rheumatology Research Foundation
Role
Principal Investigator
Start Date
October 01, 2014
End Date
September 30, 2016

Assessing whether B cell depletion interferes with methotrexate-induced immune tolerance to Myozyme

Administered By
Immunology
AwardedBy
Genzyme Corporation
Role
Principal Investigator
Start Date
December 12, 2013
End Date
December 11, 2015

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 29, 2009
End Date
July 31, 2015

MS4A Family Members in Health and Disease

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 15, 2004
End Date
May 31, 2010

CD83 Regulation of Lymphocyte Development and Function

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 20, 2004
End Date
December 31, 2008

CD22 Regulation of B Lymphocyte Function and Survival

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2003
End Date
April 30, 2008

The role of chemokines in antigen-specific immunity

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
April 01, 2002
End Date
March 31, 2006

Molecular Analysis of B-Lymphocyte Restricted Proteins

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 1998
End Date
June 30, 2004

Regulation of Leukocyte Recirculation

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 1997
End Date
December 31, 2002

Specialized center of research (SCOR) in Rheumatoid Arthritis

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 1987
End Date
August 31, 2001

Specialized Center Of Research In Rheumatoid Arthritis

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1987
End Date
August 31, 1999

Barrier To Xenotransplantation

Administered By
Pediatrics
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
February 01, 1994
End Date
June 30, 1999

The Barrier To Xenotransplantation

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
February 01, 1996
End Date
January 31, 1999

Display Memory Xenotransplantation

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
February 01, 1994
End Date
January 31, 1999

The Barrier To Xenotransplantation

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
February 01, 1993
End Date
January 31, 1999

Molecular Analysis Of B Lymphocyte - Restricted Proteins

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1994
End Date
December 31, 1998

Molecular Analysis Of B-Lymphocyte Restricted Proteins

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1988
End Date
December 31, 1998

Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Molecular Dna Analysis Facility

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 1997
End Date
January 31, 1998

Regulation Of Human Leukocyte Recirculation

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 1994
End Date
December 31, 1996
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Publications:

Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells.

Angiotensin II (AngII) promotes hypertension, atherogenesis, vascular aneurysm and impairs post-ischemic cardiac remodeling through concerted roles on vascular cells, monocytes and T lymphocytes. However, the role of AngII in B lymphocyte responses is largely unexplored. Here, we show that chronic B cell depletion (Baffr deficiency) significantly reduces atherosclerosis in Apoe -/- mice infused with AngII. While adoptive transfer of B cells in Apoe -/- /Baffr -/- mice reversed atheroprotection in the absence of AngII, infusion of AngII in B cell replenished Apoe -/- /Baffr -/- mice unexpectedly prevented the progression of atherosclerosis. Atheroprotection observed in these mice was associated with a significant increase in regulatory CD1dhiCD5+ B cells, which produced high levels of interleukin (IL)-10 (B10 cells). Replenishment of Apoe -/- /Baffr -/- mice with Il10 -/- B cells reversed AngII-induced B cell-dependent atheroprotection, thus highlighting a protective role of IL-10+ regulatory B cells in this setting. Transfer of AngII type 1A receptor deficient (Agtr1a -/-) B cells into Apoe -/- /Baffr -/- mice substantially reduced the production of IL-10 by B cells and prevented the AngII-dependent atheroprotective B cell phenotype. Consistent with the in vivo data, AngII synergized with BAFF to induce IL-10 production by B cells in vitro via AngII type 1A receptor. Our data demonstrate a previously unknown synergy between AngII and BAFF in inducing IL-10 production by B cells, resulting in atheroprotection.

Authors
Ponnuswamy, P; Joffre, J; Herbin, O; Esposito, B; Laurans, L; Binder, CJ; Tedder, TF; Zeboudj, L; Loyer, X; Giraud, A; Zhang, Y; Tedgui, A; Mallat, Z; Ait-Oufella, H
MLA Citation
Ponnuswamy, P, Joffre, J, Herbin, O, Esposito, B, Laurans, L, Binder, CJ, Tedder, TF, Zeboudj, L, Loyer, X, Giraud, A, Zhang, Y, Tedgui, A, Mallat, Z, and Ait-Oufella, H. "Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells." Scientific Reports 7.1 (June 23, 2017): 4111-.
PMID
28646220
Source
epmc
Published In
Scientific Reports
Volume
7
Issue
1
Publish Date
2017
Start Page
4111
DOI
10.1038/s41598-017-04438-6

The Regulatory B Cell Compartment Expands Transiently During Childhood and Is Contracted in Children With Autoimmunity.

Regulatory B cells that inhibit immune responses through interleukin-10 (IL-10) secretion (B10 cells) have been characterized in adult subjects with autoimmune disease. The aim of this study was to characterize B10 cells in individuals across the entire age range of normal human development and changes in their frequency and numbers in children with autoimmunity.The phenotype and numbers of B10 cells in blood were examined in healthy individuals and children with autoimmunity, using flow cytometry. B10 cell function was assessed by measuring the effect of B cell-derived IL-10 on interferon-γ (IFNγ) expression by CD4+ T cells. Serum cytokine levels were measured by enzyme-linked immunosorbent assay.The frequency of B10 cells transiently increased during childhood, when up to 30% of B cells were competent to produce IL-10, compared with the low frequencies in healthy newborns (3-4%) and adults (7-9%). The surface phenotype of B10 cells in children revealed age-dependent variability. B10 cells from children were distinct from proinflammatory cytokine-producing B cells and down-regulated IFNγ production by CD4+ T cells in vitro. Compared with age-matched healthy controls, children with autoimmunity had lower numbers and frequencies of B10 cells (decreased by 39% and 48%, respectively), higher IFNγ levels, and lower IL-21 levels in serum. IFNγ inhibited, whereas IL-21 promoted, B cell IL-10 competence in vitro.B10 cells, a functionally defined cell subset with a variable surface phenotype reflective of overall B cell development, transiently expand during childhood. B10 cell frequencies and numbers were decreased in children with autoimmunity, which may be explained in part by alterations in serum IFNγ and IL-21 that differentially regulate B10 cell development.

Authors
Kalampokis, I; Venturi, GM; Poe, JC; Dvergsten, JA; Sleasman, JW; Tedder, TF
MLA Citation
Kalampokis, I, Venturi, GM, Poe, JC, Dvergsten, JA, Sleasman, JW, and Tedder, TF. "The Regulatory B Cell Compartment Expands Transiently During Childhood and Is Contracted in Children With Autoimmunity." Arthritis & rheumatology (Hoboken, N.J.) 69.1 (January 2017): 225-238.
PMID
27429419
Source
epmc
Published In
Arthritis and Rheumatology
Volume
69
Issue
1
Publish Date
2017
Start Page
225
End Page
238
DOI
10.1002/art.39820

Nucleosome in patients with systemic sclerosis: possible association with immunological abnormalities via abnormal activation of T and B cells.

To determine the serum levels of nucleosome in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc.Serum nucleosome levels in 91 patients with SSc were examined by ELISA. The expression of Toll-like receptor (TLR) 9 in T and B cells was quantified by flow cytometric intracellular protein analysis. The effects of nucleosomes on lymphocytes were also analysed. Moreover, we assessed the effects of nucleosomes on fibrosis, using wild type and CD19-deficient bleomycin-treated mice, an experimental model for human SSc.Serum nucleosome levels were elevated in SSc compared with healthy controls and correlated positively with the extent of skin and pulmonary fibrosis and immunological abnormalities. The retrospective longitudinal analysis showed the serum nucleosome levels to be attenuated during the follow-up period. TLR9, which can be stimulated by nucleosome expression was upregulated in the affected T and B cells of patients with SSc. Moreover, nucleosome stimulation strongly increased interleukin (IL)-4 and IL-17 expression of T cells, B-cell IgG production and proliferation of lymphocytes in SSc compared with those in healthy controls. In bleomycin-induced SSc model mice, serum nucleosome levels were elevated compared with control mice. Furthermore, nucleosomes increased IgG production and proliferation of mouse B cells. Although TLR9 expression was similar between wild type and CD19-deficient splenic B cells, CD19 deficiency reduced these nucleosome effects.These results suggest that nucleosomes and its signalling in B and T cells contribute to disease development in SSc via TLR9.

Authors
Yoshizaki, A; Taniguchi, T; Saigusa, R; Fukasawa, T; Ebata, S; Numajiri, H; Nakamura, K; Yamashita, T; Takahashi, T; Toyama, T; Asano, Y; Tedder, TF; Sato, S
MLA Citation
Yoshizaki, A, Taniguchi, T, Saigusa, R, Fukasawa, T, Ebata, S, Numajiri, H, Nakamura, K, Yamashita, T, Takahashi, T, Toyama, T, Asano, Y, Tedder, TF, and Sato, S. "Nucleosome in patients with systemic sclerosis: possible association with immunological abnormalities via abnormal activation of T and B cells." Annals of the rheumatic diseases 75.10 (October 2016): 1858-1865.
PMID
26567180
Source
epmc
Published In
Annals of the rheumatic diseases
Volume
75
Issue
10
Publish Date
2016
Start Page
1858
End Page
1865
DOI
10.1136/annrheumdis-2015-207405

Galectin-1 drives lymphoma CD20 immunotherapy resistance: validation of a preclinical system to identify resistance mechanisms.

Non-Hodgkin lymphoma (NHL) is the most commonly diagnosed hematologic cancer of adults in the United States, with the vast majority of NHLs deriving from malignant B lymphocytes that express cell surface CD20. CD20 immunotherapy (rituximab) is widely used to treat NHL, even though the initial effectiveness of rituximab varies widely among patients and typically wanes over time. The mechanisms through which lymphomas initially resist or gain resistance to immunotherapy are not well established. To address this, a preclinical mouse model system was developed to comprehensively identify lymphoma transcriptomic changes that confer resistance to CD20 immunotherapy. The generation of spontaneous primary and familial lymphomas revealed that sensitivity to CD20 immunotherapy was not regulated by differences in CD20 expression, prior exposure to CD20 immunotherapy, or serial in vivo passage. An unbiased forward exome screen of these primary lymphomas was used to validate the utility of this expansive lymphoma cohort, which revealed that increased lymphoma galectin-1 (Gal-1) expression strongly correlated with resistance to immunotherapy. Genetically induced lymphoma Gal-1 expression ablated antibody-dependent lymphoma phagocytosis in vitro and lymphoma sensitivity to CD20 immunotherapy in vivo. Human NHLs also express elevated Gal-1 compared with nonmalignant lymphocytes, demonstrating the ability of this preclinical model system to identify molecular targets that could be relevant to human therapy. This study therefore established a powerful preclinical model system that permits the comprehensive identification of the dynamic lymphoma molecular network that drives resistance to immunotherapy.

Authors
Lykken, JM; Horikawa, M; Minard-Colin, V; Kamata, M; Miyagaki, T; Poe, JC; Tedder, TF
MLA Citation
Lykken, JM, Horikawa, M, Minard-Colin, V, Kamata, M, Miyagaki, T, Poe, JC, and Tedder, TF. "Galectin-1 drives lymphoma CD20 immunotherapy resistance: validation of a preclinical system to identify resistance mechanisms." Blood 127.15 (April 2016): 1886-1895.
PMID
26888257
Source
epmc
Published In
Blood
Volume
127
Issue
15
Publish Date
2016
Start Page
1886
End Page
1895
DOI
10.1182/blood-2015-11-681130

Intravital imaging of Ca(2+) signals in lymphocytes of Ca(2+) biosensor transgenic mice: indication of autoimmune diseases before the pathological onset.

Calcium ion (Ca(2+)) signaling is a typical phenomenon mediated through immune receptors, such as the B-cell antigen receptor (BCR), and it is important for their biological activities. To analyze the signaling of immune receptors together with their in vivo dynamics, we generated stable transgenic mice with the Föster/fluorescence resonance energy transfer (FRET)-based Ca(2+) indicator yellow cameleon 3.60 (YC3.60), based on the Cre/loxP system (YC3.60(flox)). We successfully obtained mice with specific YC3.60 expression in immune or nerve cells as well as mice with ubiquitous expression of this indicator. We established five-dimensional (5D) (x, y, z, time, and Ca(2+)) intravital imaging of lymphoid tissues, including the bone marrow. Furthermore, in autoimmune-prone models, the CD22(-/-) and C57BL/6- lymphoproliferation (lpr)/lpr mouse, Ca(2+) fluxes were augmented, although they did not induce autoimmune disease. Intravital imaging of Ca(2+) signals in lymphocytes may improve assessment of the risk of autoimmune diseases in model animals.

Authors
Yoshikawa, S; Usami, T; Kikuta, J; Ishii, M; Sasano, T; Sugiyama, K; Furukawa, T; Nakasho, E; Takayanagi, H; Tedder, TF; Karasuyama, H; Miyawaki, A; Adachi, T
MLA Citation
Yoshikawa, S, Usami, T, Kikuta, J, Ishii, M, Sasano, T, Sugiyama, K, Furukawa, T, Nakasho, E, Takayanagi, H, Tedder, TF, Karasuyama, H, Miyawaki, A, and Adachi, T. "Intravital imaging of Ca(2+) signals in lymphocytes of Ca(2+) biosensor transgenic mice: indication of autoimmune diseases before the pathological onset." Scientific Reports 6 (January 6, 2016): 18738-.
PMID
26732477
Source
epmc
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
18738
DOI
10.1038/srep18738

Angiotensin II mobilizes spleen monocytes to promote the development of abdominal aortic aneurysm in Apoe-/- mice

© 2014 American Heart Association, Inc. OBJECTIVE - : Abdominal aortic aneurysm (AAA) is widespread among elderly people and results in progressive expansion and rupture of the aorta with high mortality. Macrophages, which are the main population observed within the site of aneurysm, are thought to derive from circulating monocytes although no direct evidence has been provided to date. In this study, we were particularly interested in understanding the trafficking behavior of monocyte subsets in AAA and their role in disease pathogenesis. APPROACH AND RESULTS - : Using bone marrow transplantation in Apoe mice, we showed that circulating monocytes give rise to abdominal aortic macrophages in hypercholesterolemic mice submitted to angiotensin II (AngII). Detailed monitoring of monocyte compartmentalization revealed that lymphocyte antigen 6C and lymphocyte antigen 6C monocytes transiently increase in blood early after AngII infusion and differentially infiltrate the abdominal aorta. The splenic reservoir accounted for the mobilization of the 2 monocyte subsets after 3 days of AngII infusion. Spleen removal or lymphocyte deficiency in Apoe Rag2 mice similarly impaired early monocyte increase in blood in response to AngII and protected against AAA development, independently of blood pressure. Reconstitution of Apoe Rag2 mice with total splenocytes but not with B-cell-depleted splenocytes restored monocyte mobilization in response to AngII and enhanced susceptibility to AAA. CONCLUSIONS - : Taken together, the data show that lymphocyte antigen 6C and lymphocyte antigen 6C monocytes are mobilized from the spleen in response to AngII. Intriguingly, the process is dependent on the presence of B cells and significantly contributes to the development of AAA and the occurrence of aortic rupture.

Authors
Mellak, S; Ait-Oufella, H; Esposito, B; Loyer, X; Poirier, M; Tedder, TF; Tedgui, A; Mallat, Z; Potteaux, S
MLA Citation
Mellak, S, Ait-Oufella, H, Esposito, B, Loyer, X, Poirier, M, Tedder, TF, Tedgui, A, Mallat, Z, and Potteaux, S. "Angiotensin II mobilizes spleen monocytes to promote the development of abdominal aortic aneurysm in Apoe-/- mice." Arteriosclerosis, Thrombosis, and Vascular Biology 35.2 (January 1, 2016): 378-388.
Source
scopus
Published In
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume
35
Issue
2
Publish Date
2016
Start Page
378
End Page
388
DOI
10.1161/ATVBAHA.114.304389

Natural IgM Switches the Function of Lipopolysaccharide-Activated Murine Bone Marrow-Derived Dendritic Cells to a Regulatory Dendritic Cell That Suppresses Innate Inflammation.

We have previously shown that polyclonal natural IgM protects mice from renal ischemia/reperfusion injury (IRI) by inhibiting the reperfusion inflammatory response. We hypothesized that a potential mechanism involved IgM modulation of dendritic cells (DC), as we observed high IgM binding to splenic DC. To test this hypothesis, we pretreated bone marrow-derived DC (BMDC) with polyclonal murine or human IgM prior to LPS activation and demonstrated that 0.5 × 10(6) IgM/LPS-pretreated BMDC, when injected into wild-type C57BL/6 mice 24 h before renal ischemia, protect mice from developing renal IRI. We show that this switching of LPS-activated BMDC to a regulatory phenotype requires modulation of BMDC function that is mediated by IgM binding to nonapoptotic BMDC receptors. Regulatory BMDC require IL-10 and programmed death 1 as well as downregulation of CD40 and p65 NF-κB phosphorylation to protect in renal IRI. Blocking the programmed death ligand 1 binding site just before i.v. injection of IgM/LPS-pretreated BMDC or using IL-10 knockout BMDC fails to induce protection. Similarly, IgM/LPS-pretreated BMDC are rendered nonprotective by increasing CD40 expression and phosphorylation of p65 NF-κB. How IgM/LPS regulatory BMDC suppress in vivo ischemia-induced innate inflammation remains to be determined. However, we show that suppression is dependent on other in vivo regulatory mechanisms in the host, that is, CD25(+) T cells, B cells, IL-10, and circulating IgM. There was no increase in Foxp3(+) regulatory T cells in the spleen either before or after renal IRI. Collectively, these findings show that natural IgM anti-leukocyte Abs can switch BMDC to a regulatory phenotype despite the presence of LPS that ordinarily induces BMDC maturation.

Authors
Lobo, PI; Schlegel, KH; Bajwa, A; Huang, L; Kurmaeva, E; Wang, B; Ye, H; Tedder, TF; Kinsey, GR; Okusa, MD
MLA Citation
Lobo, PI, Schlegel, KH, Bajwa, A, Huang, L, Kurmaeva, E, Wang, B, Ye, H, Tedder, TF, Kinsey, GR, and Okusa, MD. "Natural IgM Switches the Function of Lipopolysaccharide-Activated Murine Bone Marrow-Derived Dendritic Cells to a Regulatory Dendritic Cell That Suppresses Innate Inflammation." Journal of immunology (Baltimore, Md. : 1950) 195.11 (December 2015): 5215-5226.
PMID
26519533
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
195
Issue
11
Publish Date
2015
Start Page
5215
End Page
5226
DOI
10.4049/jimmunol.1500052

Authors' reply.

Authors
Kountikov, E; Fujisawa, Y; Tedder, TF
MLA Citation
Kountikov, E, Fujisawa, Y, and Tedder, TF. "Authors' reply." The American journal of pathology 185.11 (November 2015): 3127-3128. (Letter)
PMID
26506475
Source
epmc
Published In
The American journal of pathology
Volume
185
Issue
11
Publish Date
2015
Start Page
3127
End Page
3128
DOI
10.1016/j.ajpath.2015.09.002

Regulatory B10 cell development and function.

B cells are known to instigate and promulgate immune responses by producing antibodies and presenting antigens to T cells. However, a rare but potent B-cell subset in both humans and mice is capable of inhibiting immune responses through the production of the anti-inflammatory cytokine IL-10. Regulatory B cells do not express any unique combination of surface markers but instead represent a small population of B cells that have acquired the unique ability to produce IL-10. This numerically rare B-cell subset is therefore functionally referred to as 'B10 cells' to reflect both their molecular program and the fact that their anti-inflammatory effects in models of autoimmunity, infection and cancer are solely attributable to IL-10 production. As with most B cells, B10 cell development and function appear to be predominantly, if not exclusively, driven by antigen-receptor signals. Once generated, B10 cells respond to both innate and adaptive immune signals, with a requirement for antigen-specific local interactions with T cells to induce IL-10 production and to provide optimal immune suppression in mouse models of autoimmune disease. B10 cells therefore provide an antigen-specific mechanism for delivering IL-10 locally to sites of immune activation and inflammation. The ability of B10 cells to regulate innate and adaptive immune responses makes them an ideal therapeutic target for the treatment of many immune-related disorders.

Authors
Lykken, JM; Candando, KM; Tedder, TF
MLA Citation
Lykken, JM, Candando, KM, and Tedder, TF. "Regulatory B10 cell development and function." International immunology 27.10 (October 2015): 471-477. (Review)
PMID
26254185
Source
epmc
Published In
International Immunology
Volume
27
Issue
10
Publish Date
2015
Start Page
471
End Page
477
DOI
10.1093/intimm/dxv046

Introduction: Regulatory B Cell Special Issue-making all the pieces fit.

Authors
Tedder, TF
MLA Citation
Tedder, TF. "Introduction: Regulatory B Cell Special Issue-making all the pieces fit." International immunology 27.10 (October 2015): 467-470.
PMID
26419472
Source
epmc
Published In
International Immunology
Volume
27
Issue
10
Publish Date
2015
Start Page
467
End Page
470
DOI
10.1093/intimm/dxv047

The Tumor Microenvironment Regulates CD19 and CD20 Immunotherapy for Lymphoma.

B cells have diverse functions during immune responses, including antibody production, antigen presentation, and cytokine secretion. Multiple lymphomas and leukemias derive from malignant B cells, so therapies that deplete B cells are clinically important, particularly antibodies targeting the B cell-specific surface molecules CD19 and CD20. Macrophages are the principal mediators of CD19 and CD20 monoclonal antibody-dependent B-cell and lymphoma depletion in mice through Fcγ receptor-dependent phagocytosis. Thereby, the extent of CD19 or CD20 antibody-induced B cell and tumor depletion in vivo is influenced by molecular changes within tumors and genetic variations between individuals. In addition to Fcγ receptor polymorphisms, lymphoma- and regulatory B cell-derived cytokine production and macrophage localization and function within tumor microenvironments influence tumor clearance. Given the dynamic interactions of these factors, the identification of effector cell and tumor microenvironment genetic alterations will identify molecular targets that enhance immunotherapies for the treatment of human diseases.

Authors
Lykken, JM; Tedder, TF
MLA Citation
Lykken, JM, and Tedder, TF. "The Tumor Microenvironment Regulates CD19 and CD20 Immunotherapy for Lymphoma." Cancer journal (Sudbury, Mass.) 21.4 (July 2015): 351-356. (Review)
PMID
26222089
Source
epmc
Published In
Cancer Journal
Volume
21
Issue
4
Publish Date
2015
Start Page
351
End Page
356
DOI
10.1097/ppo.0000000000000137

B lymphocytes in neuromyelitis optica.

Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the CNS that predominantly affects the spinal cord and optic nerves. A majority (approximately 75%) of patients with NMO are seropositive for autoantibodies against the astrocyte water channel aquaporin-4 (AQP4). These autoantibodies are predominantly IgG1, and considerable evidence supports their pathogenicity, presumably by binding to AQP4 on CNS astrocytes, resulting in astrocyte injury and inflammation. Convergent clinical and laboratory-based investigations have indicated that B cells play a fundamental role in NMO immunopathology. Multiple mechanisms have been hypothesized: AQP4 autoantibody production, enhanced proinflammatory B cell and plasmablast activity, aberrant B cell tolerance checkpoints, diminished B cell regulatory function, and loss of B cell anergy. Accordingly, many current off-label therapies for NMO deplete B cells or modulate their activity. Understanding the role and mechanisms whereby B cells contribute to initiation, maintenance, and propagation of disease activity is important to advancing our understanding of NMO pathogenesis and developing effective disease-specific therapies.

Authors
Bennett, JL; O'Connor, KC; Bar-Or, A; Zamvil, SS; Hemmer, B; Tedder, TF; von Büdingen, H-C; Stuve, O; Yeaman, MR; Smith, TJ; Stadelmann, C
MLA Citation
Bennett, JL, O'Connor, KC, Bar-Or, A, Zamvil, SS, Hemmer, B, Tedder, TF, von Büdingen, H-C, Stuve, O, Yeaman, MR, Smith, TJ, and Stadelmann, C. "B lymphocytes in neuromyelitis optica." Neurology(R) neuroimmunology & neuroinflammation 2.3 (June 2015): e104-. (Review)
PMID
25977932
Source
epmc
Published In
Neurology: Neuroimmunology and Neuroinflammation
Volume
2
Issue
3
Publish Date
2015
Start Page
e104
DOI
10.1212/nxi.0000000000000104

L-selectin shedding is activated specifically within transmigrating pseudopods of monocytes to regulate cell polarity in vitro.

L-selectin is a cell adhesion molecule that tethers free-flowing leukocytes from the blood to luminal vessel walls, facilitating the initial stages of their emigration from the circulation toward an extravascular inflammatory insult. Following shear-resistant adhesion to the vessel wall, L-selectin has frequently been reported to be rapidly cleaved from the plasma membrane (known as ectodomain shedding), with little knowledge of the timing or functional consequence of this event. Using advanced imaging techniques, we observe L-selectin shedding occurring exclusively as primary human monocytes actively engage in transendothelial migration (TEM). Moreover, the shedding was localized to transmigrating pseudopods within the subendothelial space. By capturing monocytes in midtransmigration, we could monitor the subcellular distribution of L-selectin and better understand how ectodomain shedding might contribute to TEM. Mechanistically, L-selectin loses association with calmodulin (CaM; a negative regulator of shedding) specifically within transmigrating pseudopods. In contrast, L-selectin/CaM interaction remained intact in nontransmigrated regions of monocytes. We show phosphorylation of L-selectin at Ser 364 is critical for CaM dissociation, which is also restricted to the transmigrating pseudopod. Pharmacological or genetic inhibition of L-selectin shedding significantly increased pseudopodial extensions in transmigrating monocytes, which potentiated invasive behavior during TEM and prevented the establishment of front/back polarity for directional migration persistence once TEM was complete. We conclude that L-selectin shedding directly regulates polarity in transmigrated monocytes, which affirms an active role for this molecule in driving later stages of the multistep adhesion cascade.

Authors
Rzeniewicz, K; Newe, A; Rey Gallardo, A; Davies, J; Holt, MR; Patel, A; Charras, GT; Stramer, B; Molenaar, C; Tedder, TF; Parsons, M; Ivetic, A
MLA Citation
Rzeniewicz, K, Newe, A, Rey Gallardo, A, Davies, J, Holt, MR, Patel, A, Charras, GT, Stramer, B, Molenaar, C, Tedder, TF, Parsons, M, and Ivetic, A. "L-selectin shedding is activated specifically within transmigrating pseudopods of monocytes to regulate cell polarity in vitro." Proceedings of the National Academy of Sciences of the United States of America 112.12 (March 9, 2015): E1461-E1470.
PMID
25775539
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
12
Publish Date
2015
Start Page
E1461
End Page
E1470
DOI
10.1073/pnas.1417100112

A spontaneous deletion within the desmoglein 3 extracellular domain of mice results in hypomorphic protein expression, immunodeficiency, and a wasting disease phenotype.

Desmoglein 3 is a transmembrane component of desmosome complexes that mediate epidermal cell-to-cell adhesion and tissue integrity. Antibody blockade of desmoglein 3 function in pemphigus vulgaris patients leads to skin blistering (acantholysis) and oral mucosa lesions. Desmoglein 3 deficiency in mice leads to a phenotype characterized by cyclic alopecia in addition to the dramatic skin and mucocutaneous acantholysis observed in pemphigus patients. In this study, mice that developed an overt squeaky (sqk) phenotype were identified with obstructed airways, cyclic hair loss, and severe immunodeficiency subsequent to the development of oral lesions and malnutrition. Single-nucleotide polymorphism-based quantitative trait loci mapping revealed a genetic deletion that resulted in expression of a hypomorphic desmoglein 3 protein with a truncation of an extracellular cadherin domain. Because hypomorphic expression of a truncated desmoglein 3 protein led to a spectrum of severe pathology not observed in mice deficient in desmoglein 3, similar human genetic alterations may also disrupt desmosome function and induce a disease course distinct from pathogenesis of pemphigus vulgaris.

Authors
Kountikov, EI; Poe, JC; Maclver, NJ; Rathmell, JC; Tedder, TF
MLA Citation
Kountikov, EI, Poe, JC, Maclver, NJ, Rathmell, JC, and Tedder, TF. "A spontaneous deletion within the desmoglein 3 extracellular domain of mice results in hypomorphic protein expression, immunodeficiency, and a wasting disease phenotype." The American Journal of Pathology 185.3 (March 2015): 617-630.
PMID
25542773
Source
epmc
Published In
The American journal of pathology
Volume
185
Issue
3
Publish Date
2015
Start Page
617
End Page
630
DOI
10.1016/j.ajpath.2014.10.025

Angiotensin II mobilizes spleen monocytes to promote the development of abdominal aortic aneurysm in Apoe-/- mice.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is widespread among elderly people and results in progressive expansion and rupture of the aorta with high mortality. Macrophages, which are the main population observed within the site of aneurysm, are thought to derive from circulating monocytes although no direct evidence has been provided to date. In this study, we were particularly interested in understanding the trafficking behavior of monocyte subsets in AAA and their role in disease pathogenesis. APPROACH AND RESULTS: Using bone marrow transplantation in Apoe(-/-) mice, we showed that circulating monocytes give rise to abdominal aortic macrophages in hypercholesterolemic mice submitted to angiotensin II (AngII). Detailed monitoring of monocyte compartmentalization revealed that lymphocyte antigen 6C(high) and lymphocyte antigen 6C(low) monocytes transiently increase in blood early after AngII infusion and differentially infiltrate the abdominal aorta. The splenic reservoir accounted for the mobilization of the 2 monocyte subsets after 3 days of AngII infusion. Spleen removal or lymphocyte deficiency in Apoe(-/-) Rag2(-/-) mice similarly impaired early monocyte increase in blood in response to AngII and protected against AAA development, independently of blood pressure. Reconstitution of Apoe(-/-) Rag2(-/-) mice with total splenocytes but not with B-cell-depleted splenocytes restored monocyte mobilization in response to AngII and enhanced susceptibility to AAA. CONCLUSIONS: Taken together, the data show that lymphocyte antigen 6C(high) and lymphocyte antigen 6C(low) monocytes are mobilized from the spleen in response to AngII. Intriguingly, the process is dependent on the presence of B cells and significantly contributes to the development of AAA and the occurrence of aortic rupture.

Authors
Mellak, S; Ait-Oufella, H; Esposito, B; Loyer, X; Poirier, M; Tedder, TF; Tedgui, A; Mallat, Z; Potteaux, S
MLA Citation
Mellak, S, Ait-Oufella, H, Esposito, B, Loyer, X, Poirier, M, Tedder, TF, Tedgui, A, Mallat, Z, and Potteaux, S. "Angiotensin II mobilizes spleen monocytes to promote the development of abdominal aortic aneurysm in Apoe-/- mice." Arteriosclerosis, thrombosis, and vascular biology 35.2 (February 2015): 378-388.
PMID
25524776
Source
epmc
Published In
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume
35
Issue
2
Publish Date
2015
Start Page
378
End Page
388
DOI
10.1161/atvbaha.114.304389

B10 cells: a functionally defined regulatory B cell subset.

B cells are commonly thought to enhance inflammatory immune responses. However, specific regulatory B cell subsets recently were identified that downregulate adaptive and innate immunity, inflammation, and autoimmunity through diverse molecular mechanisms. In both mice and humans, a rare, but specific, subset of regulatory B cells is functionally characterized by its capacity to produce IL-10, a potent inhibitory cytokine. For clarity, this regulatory B cell subset has been labeled as B10 cells, because their ability to downregulate immune responses and inflammatory disease is fully attributable to IL-10, and their absence or loss exacerbates disease symptoms in mouse models. This review preferentially focuses on what is known about mouse B10 cell development, phenotype, and effector function, as well as on mechanistic studies that demonstrated their functional importance during inflammation, autoimmune disease, and immune responses.

Authors
Tedder, TF
MLA Citation
Tedder, TF. "B10 cells: a functionally defined regulatory B cell subset." Journal of immunology (Baltimore, Md. : 1950) 194.4 (February 2015): 1395-1401. (Review)
PMID
25663677
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
194
Issue
4
Publish Date
2015
Start Page
1395
End Page
1401
DOI
10.4049/jimmunol.1401329

[IL-21 induces regulatory B cell differentiation and immunosuppressive effect through cognate interaction with T cells].

For a long time, it has been thinking that B cells regulate immune responses by producing antigen-specific antibodies. However, previous studies have revealed that specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Recently, our study showed that mouse CD1d(hi)CD5(+) B cell subsets mainly produce IL-10. Therefore, we named these populations B10 cells. In our previous studies have also indicated that human B10 cells with the ability to express the inhibitory cytokine interleukin (IL)-10 have been identified. Although it is rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using an experimental autoimmune encephalomyelitis, which is a mouse model for multiple sclerosis, we have shown that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. In addition, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.

Authors
Yoshizaki, A; Tedder, TF
MLA Citation
Yoshizaki, A, and Tedder, TF. "[IL-21 induces regulatory B cell differentiation and immunosuppressive effect through cognate interaction with T cells]." Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 38.1 (January 2015): 57-64.
PMID
25765689
Source
epmc
Published In
Nihon Rinsho Meneki Gakkai kaishi = Japanese journal of clinical immunology
Volume
38
Issue
1
Publish Date
2015
Start Page
57
End Page
64
DOI
10.2177/jsci.38.57

Autoimmunity: Regulatory B cells—IL-35 and IL-21 regulate the regulators

Authors
Tedder, TF; Leonard, WJ
MLA Citation
Tedder, TF, and Leonard, WJ. "Autoimmunity: Regulatory B cells—IL-35 and IL-21 regulate the regulators." Nature Reviews Rheumatology 10.11 (September 16, 2014): 636-636.
Source
crossref
Published In
Nature Reviews Rheumatology
Volume
10
Issue
11
Publish Date
2014
Start Page
636
End Page
636
DOI
10.1038/nrrheum.2014.163

Autoimmunity: regulatory B cells--IL-35 and IL-21 regulate the regulators.

IL-21 regulates the activity and number of IL-10-producing regulatory B cells (B10 cells) that modulate immune responses and limit diverse autoimmune diseases. A new study demonstrates that IL-35 has a similar function. Identifying regulatory circuits that control B10-cell function in vivo might open the door to future treatments for autoimmune diseases.

Authors
Tedder, TF; Leonard, WJ
MLA Citation
Tedder, TF, and Leonard, WJ. "Autoimmunity: regulatory B cells--IL-35 and IL-21 regulate the regulators." Nature reviews. Rheumatology 10.8 (August 2014): 452-453.
PMID
24934192
Source
epmc
Published In
Nature Reviews Rheumatology
Volume
10
Issue
8
Publish Date
2014
Start Page
452
End Page
453
DOI
10.1038/nrrheum.2014.95

Acute and chronic B cell depletion disrupts CD4+ and CD8+ T cell homeostasis and expansion during acute viral infection in mice.

B cells provide humoral protection against pathogens and promote cellular immunity through diverse nonclassical effector functions. To assess B cell function in promoting T cell homeostasis, mature B cells were either acutely or chronically depleted in mice using CD20 mAb. Acute B cell depletion in either 2- or 4-mo-old mice significantly reduced spleen and lymph node CD4(+) and CD8(+) T cell numbers, including naive, activated, and Foxp3(+)CD25(+)CD4(+) regulatory T cell subsets. The numbers of IFN-γ- and TNF-α-producing T cells were also significantly reduced. Chronic B cell depletion for 6 mo in aged naive mice resulted in a 40-70% reduction in activated CD4(+) and CD8(+) T cell numbers and 20-50% reductions in IFN-γ-producing T cells. Therefore, B cells were necessary for maintaining naive CD4(+) and CD8(+) T cell homeostasis for subsequent optimal T cell expansion in young and old mice. To determine the significance of this finding, a week of B cell depletion in 4-mo-old mice was followed by acute viral infection with lymphocytic choriomeningitis virus Armstrong. Despite their expansion, activated and cytokine-producing CD4(+) and CD8(+) T cell numbers were still significantly reduced 1 wk later. Moreover, viral peptide-specific CD4(+) and CD8(+) T cell numbers and effector cell development were significantly reduced in mice lacking B cells, whereas lymphocytic choriomeningitis virus titers were dramatically increased. Thus, T cell function is maintained in B cell-depleted mice, but B cells are required for optimal CD4(+) and CD8(+) T cell homeostasis, activation, and effector development in vivo, particularly during responses to acute viral infection.

Authors
Lykken, JM; DiLillo, DJ; Weimer, ET; Roser-Page, S; Heise, MT; Grayson, JM; Weitzmann, MN; Tedder, TF
MLA Citation
Lykken, JM, DiLillo, DJ, Weimer, ET, Roser-Page, S, Heise, MT, Grayson, JM, Weitzmann, MN, and Tedder, TF. "Acute and chronic B cell depletion disrupts CD4+ and CD8+ T cell homeostasis and expansion during acute viral infection in mice." Journal of immunology (Baltimore, Md. : 1950) 193.2 (July 2014): 746-756.
PMID
24928986
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
193
Issue
2
Publish Date
2014
Start Page
746
End Page
756
DOI
10.4049/jimmunol.1302848

A crucial role of L-selectin in C protein-induced experimental polymyositis in mice.

To investigate the role of adhesion molecules in C protein-induced myositis (CIM), a murine model of polymyositis (PM).CIM was induced in wild-type mice, L-selectin-deficient (L-selectin(-/-) ) mice, intercellular adhesion molecule 1 (ICAM-1)-deficient (ICAM-1(-/-) ) mice, and mice deficient in both L-selectin and ICAM-1 (L-selectin(-/-) ICAM-1(-/-) mice). Myositis severity, inflammatory cell infiltration, and messenger RNA expression in the inflamed muscles were analyzed. The effect of dendritic polyglycerol sulfate, a synthetic inhibitor that suppresses the function of L-selectin and endothelial P-selectin, was also examined.L-selectin(-/-) mice and L-selectin(-/-) ICAM-1(-/-) mice developed significantly less severe myositis compared to wild-type mice, while ICAM-1 deficiency did not inhibit the development of myositis. L-selectin(-/-) mice that received wild-type T cells developed myositis. Treatment with dendritic polyglycerol sulfate significantly diminished the severity of myositis in wild-type mice compared to treatment with control.These data indicate that L-selectin plays a major role in the development of CIM, whereas ICAM-1 plays a lesser role, if any, in the development of CIM. L-selectin-targeted therapy may be a candidate for the treatment of PM.

Authors
Oishi, K; Hamaguchi, Y; Matsushita, T; Hasegawa, M; Okiyama, N; Dernedde, J; Weinhart, M; Haag, R; Tedder, TF; Takehara, K; Kohsaka, H; Fujimoto, M
MLA Citation
Oishi, K, Hamaguchi, Y, Matsushita, T, Hasegawa, M, Okiyama, N, Dernedde, J, Weinhart, M, Haag, R, Tedder, TF, Takehara, K, Kohsaka, H, and Fujimoto, M. "A crucial role of L-selectin in C protein-induced experimental polymyositis in mice." Arthritis & rheumatology (Hoboken, N.J.) 66.7 (July 2014): 1864-1871.
PMID
24644046
Source
epmc
Published In
Arthritis and Rheumatology
Volume
66
Issue
7
Publish Date
2014
Start Page
1864
End Page
1871
DOI
10.1002/art.38630

A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels.

Signaling through the BCR can drive B cell activation and contribute to B cell differentiation into Ab-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients. We have previously shown that the transcription factor Ets1 can restrain B cell differentiation into plasma cells. In this study, we tested the roles of the BCR and inhibitory receptors in controlling the expression of Ets1 in mouse B cells. We found that Ets1 is downregulated in B cells by BCR or TLR signaling through a pathway dependent on PI3K, Btk, IKK2, and JNK. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP1) or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation. Our findings indicate that downregulation of Ets1 occurs in response to B cell activation via either BCR or TLR signaling, thereby allowing B cell differentiation and that the maintenance of Ets1 expression is an important function of the inhibitory Lyn → CD22/SiglecG → SHP1 pathway in B cells.

Authors
Luo, W; Mayeux, J; Gutierrez, T; Russell, L; Getahun, A; Müller, J; Tedder, T; Parnes, J; Rickert, R; Nitschke, L; Cambier, J; Satterthwaite, AB; Garrett-Sinha, LA
MLA Citation
Luo, W, Mayeux, J, Gutierrez, T, Russell, L, Getahun, A, Müller, J, Tedder, T, Parnes, J, Rickert, R, Nitschke, L, Cambier, J, Satterthwaite, AB, and Garrett-Sinha, LA. "A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels." Journal of immunology (Baltimore, Md. : 1950) 193.2 (July 2014): 909-920.
PMID
24929000
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
193
Issue
2
Publish Date
2014
Start Page
909
End Page
920
DOI
10.4049/jimmunol.1400666

B10 cell regulation of health and disease.

While B cells are traditionally regarded as promoters of the immune response via antibody secretion and pro-inflammatory cytokine production, recent studies have also confirmed an important role for B-cell-mediated negative regulation of immunity. Tremendous advances in the characterization of the mechanisms by which regulatory B cells function has led to the identification of a novel subset of regulatory B cells known as B10 cells, which regulate immune responses through the production of the anti-inflammatory cytokine interleukin-10 (IL-10). B10 cells are best defined by their functional ability to produce IL-10, as they are not confined to any particular phenotypic subset. B10 cells function in an antigen-specific manner that requires cognate interactions with T cells in vivo to regulate immune responses and have been demonstrated to be potent regulators of allergic and autoimmune disease, cancer, infection, and transplant rejection. Importantly, the recent discovery of human B10 cells has accelerated this field to the forefront of clinical research where the possibility of harnessing the regulatory potential of B10 cells for treatment of aberrant immune responses and diseases may become feasible.

Authors
Candando, KM; Lykken, JM; Tedder, TF
MLA Citation
Candando, KM, Lykken, JM, and Tedder, TF. "B10 cell regulation of health and disease." Immunological reviews 259.1 (May 2014): 259-272. (Review)
PMID
24712471
Source
epmc
Published In
Immunological Reviews
Volume
259
Issue
1
Publish Date
2014
Start Page
259
End Page
272
DOI
10.1111/imr.12176

Heterotropic modulation of selectin affinity by allosteric antibodies affects leukocyte rolling.

Selectins are a family of adhesion receptors designed for efficient leukocyte tethering to the endothelium under shear. As a key property to resist premature bond disruption, selectin adhesiveness is enhanced by tensile forces that promote the conversion of a bent into an extended conformation of the N-terminal lectin and epidermal growth factor-like domains. Conformation-specific Abs have been invaluable in deciphering the activation mechanism of integrins, but similar reagents are not available for selectins. In this study, we show that the anti-human L-selectin mAbs DREG-55 and LAM1-5 but not DREG-56, DREG-200, or LAM1-1 heterotropically modulate adhesion presumably by stabilizing the extended receptor conformation. Force-free affinity assays, flow chamber, and microkinetic studies reveal a ligand-specific modulation of L-selectin affinity by DREG-55 mAb, resulting in a dramatic decrease of rolling velocity under flow. Furthermore, secondary tethering of polymorphonuclear cells was blocked by DREG-200 but significantly boosted by DREG-55 mAb. The results emphasize the need for a new classification for selectin Abs and introduce the new concept of heterotropic modulation of receptor function.

Authors
Riese, SB; Kuehne, C; Tedder, TF; Hallmann, R; Hohenester, E; Buscher, K
MLA Citation
Riese, SB, Kuehne, C, Tedder, TF, Hallmann, R, Hohenester, E, and Buscher, K. "Heterotropic modulation of selectin affinity by allosteric antibodies affects leukocyte rolling." Journal of immunology (Baltimore, Md. : 1950) 192.4 (February 2014): 1862-1869.
PMID
24431230
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
192
Issue
4
Publish Date
2014
Start Page
1862
End Page
1869
DOI
10.4049/jimmunol.1302147

EndoU is a novel regulator of AICD during peripheral B cell selection.

Balanced transmembrane signals maintain a competent peripheral B cell pool limited in self-reactive B cells that may produce pathogenic autoantibodies. To identify molecules regulating peripheral B cell survival and tolerance to self-antigens (Ags), a gene modifier screen was performed with B cells from CD22-deficient C57BL/6 (CD22(-/-[B6])) mice that undergo activation-induced cell death (AICD) and fail to up-regulate c-Myc expression after B cell Ag receptor ligation. Likewise, lysozyme auto-Ag-specific B cells in Ig(Tg) hen egg lysozyme (HEL) transgenic mice inhabit the spleen but undergo AICD after auto-Ag encounter. This gene modifier screen identified EndoU, a single-stranded RNA-binding protein of ancient origin, as a major regulator of B cell survival in both models. EndoU gene disruption prevents AICD and normalizes c-Myc expression. These findings reveal that EndoU is a critical regulator of an unexpected and novel RNA-dependent pathway controlling peripheral B cell survival and Ag responsiveness that may contribute to peripheral B cell tolerance.

Authors
Poe, JC; Kountikov, EI; Lykken, JM; Natarajan, A; Marchuk, DA; Tedder, TF
MLA Citation
Poe, JC, Kountikov, EI, Lykken, JM, Natarajan, A, Marchuk, DA, and Tedder, TF. "EndoU is a novel regulator of AICD during peripheral B cell selection." J Exp Med 211.1 (January 13, 2014): 57-69.
PMID
24344237
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
211
Issue
1
Publish Date
2014
Start Page
57
End Page
69
DOI
10.1084/jem.20130648

A reevaluation of CD22 expression in human lung cancer.

CD22 is a transmembrane glycoprotein expressed by mature B cells. It inhibits signal transduction by the B-cell receptor and its coreceptor CD19. Recent reports indicate that most human lung cancer cells and cell lines express CD22, making it an important new therapeutic target for lung cancer. The objective of our studies was to independently validate these results with the goal of testing the efficacy of our CD22 immunotoxins on lung cancer cell lines. As determined by quantitative real-time PCR analysis, we found that levels of CD22 mRNA in a panel of human lung cancer cell lines were 200 to 60,000-fold lower than those observed in the human CD22(+) Burkitt lymphoma cells, Daudi. Using flow cytometry with a panel of CD22 monoclonal antibodies and Western blot analyses, we could not detect surface or intracellular expression of CD22 protein in a panel of lung cancer cell lines. In addition, the in vitro proliferation of the lung tumor cell lines was not affected by either CD22 antibodies or our highly potent anti-CD22 immunotoxin. In contrast, CD22(+) Daudi cells expressed high levels of CD22 mRNA and protein, and were sensitive to our CD22 immunotoxin. Importantly, primary non-small cell lung cancers from more than 250 patient specimens did not express detectable levels of CD22 protein as assessed by immunohistochemistry. We conclude that CD22 is not expressed at measurable levels on the surface of lung cancer cells, and that these cells cannot be killed by anti-CD22 immunotoxins.

Authors
Pop, LM; Barman, S; Shao, C; Poe, JC; Venturi, GM; Shelton, JM; Pop, IV; Gerber, DE; Girard, L; Liu, X-Y; Behrens, C; Rodriguez-Canales, J; Liu, H; Wistuba, II; Richardson, JA; Minna, JD; Tedder, TF; Vitetta, ES
MLA Citation
Pop, LM, Barman, S, Shao, C, Poe, JC, Venturi, GM, Shelton, JM, Pop, IV, Gerber, DE, Girard, L, Liu, X-Y, Behrens, C, Rodriguez-Canales, J, Liu, H, Wistuba, II, Richardson, JA, Minna, JD, Tedder, TF, and Vitetta, ES. "A reevaluation of CD22 expression in human lung cancer." Cancer Res 74.1 (January 1, 2014): 263-271.
PMID
24395821
Source
pubmed
Published In
Cancer Research
Volume
74
Issue
1
Publish Date
2014
Start Page
263
End Page
271
DOI
10.1158/0008-5472.CAN-13-1436

Autoimmunity: Regulatory B cells - IL-35 and IL-21 regulate the regulators

Authors
Tedder, TF; Leonard, WJ
MLA Citation
Tedder, TF, and Leonard, WJ. "Autoimmunity: Regulatory B cells - IL-35 and IL-21 regulate the regulators." Nature Reviews Rheumatology 10.8 (January 1, 2014): 452-453.
Source
scopus
Published In
Nature Reviews Rheumatology
Volume
10
Issue
8
Publish Date
2014
Start Page
452
End Page
453
DOI
10.1038/nrrheum.2014.95

Germinal center B cell depletion diminishes CD4+ follicular T helper cells in autoimmune mice.

BACKGROUND: Continuous support from follicular CD4(+) T helper (Tfh) cells drives germinal center (GC) responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization. METHODS AND FINDING: Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model. CONCLUSION: These data suggest that mature Tfh cells require signals from GC B cells to sustain their optimal numbers and function in both autoimmune and immunization models. Thus, immunotherapies targeting B cells in autoimmune disease may affect pathogenic Tfh cells.

Authors
Yusuf, I; Stern, J; McCaughtry, TM; Gallagher, S; Sun, H; Gao, C; Tedder, T; Carlesso, G; Carter, L; Herbst, R; Wang, Y
MLA Citation
Yusuf, I, Stern, J, McCaughtry, TM, Gallagher, S, Sun, H, Gao, C, Tedder, T, Carlesso, G, Carter, L, Herbst, R, and Wang, Y. "Germinal center B cell depletion diminishes CD4+ follicular T helper cells in autoimmune mice." PloS one 9.8 (January 2014): e102791-.
PMID
25101629
Source
epmc
Published In
PloS one
Volume
9
Issue
8
Publish Date
2014
Start Page
e102791
DOI
10.1371/journal.pone.0102791

B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction

Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6C hi monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell-selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.© 2013 Nature America, Inc. All rights reserved.

Authors
Zouggari, Y; Ait-Oufella, H; Bonnin, P; Simon, T; Sage, AP; Guérin, C; Vilar, J; Caligiuri, G; Tsiantoulas, D; Laurans, L; Dumeau, E; Kotti, S; Bruneval, P; Charo, IF; Binder, CJ; Danchin, N; Tedgui, A; Tedder, TF; Silvestre, JS; Mallat, Z
MLA Citation
Zouggari, Y, Ait-Oufella, H, Bonnin, P, Simon, T, Sage, AP, Guérin, C, Vilar, J, Caligiuri, G, Tsiantoulas, D, Laurans, L, Dumeau, E, Kotti, S, Bruneval, P, Charo, IF, Binder, CJ, Danchin, N, Tedgui, A, Tedder, TF, Silvestre, JS, and Mallat, Z. "B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction." Nature Medicine 19.10 (October 1, 2013): 1273-1280.
Source
scopus
Published In
Nature Medicine
Volume
19
Issue
10
Publish Date
2013
Start Page
1273
End Page
1280
DOI
10.1038/nm.3284

Peritoneal cavity regulatory B cells (B10 cells) modulate IFN-γ+CD4+ T cell numbers during colitis development in mice.

The spleen regulatory B cell subset with the functional capacity to express IL-10 (B10 cells) modulates both immune responses and autoimmune disease severity. However, the peritoneal cavity also contains relatively high frequencies of functionally defined IL-10-competent B10 cells. In this study, peritoneal cavity B10 cells shared similar cell surface phenotypes with their spleen counterparts. However, peritoneal cavity B10 cells were 10-fold more frequent among B cells than occurred within the spleen, intestinal tract, or mesenteric lymph nodes and were present at higher proportions among the phenotypically defined peritoneal B1a > B1b > B2 cell subpopulations. The development or localization of B10 cells within the peritoneal cavity was not dependent on the presence of commensal microbiota, T cells, IL-10 or B10 cell IL-10 production, or differences between their fetal liver or adult bone marrow progenitor cell origins. The BCR repertoire of peritoneal cavity B10 cells was diverse, as occurs in the spleen, and predominantly included germline-encoded VH and VL regions commonly found in either the conventional or B1 B cell compartments. Thereby, the capacity to produce IL-10 appears to be an intrinsic functional property acquired by clonally diverse B cells. Importantly, IL-10 production by peritoneal cavity B cells significantly reduced disease severity in spontaneous and induced models of colitis by regulating neutrophil infiltration, colitogenic CD4(+) T cell activation, and proinflammatory cytokine production during colitis onset. Thus, the numerically small B10 cell subset within the peritoneal cavity has regulatory function and is important for maintaining homeostasis within gastrointestinal tissues and the immune system.

Authors
Maseda, D; Candando, KM; Smith, SH; Kalampokis, I; Weaver, CT; Plevy, SE; Poe, JC; Tedder, TF
MLA Citation
Maseda, D, Candando, KM, Smith, SH, Kalampokis, I, Weaver, CT, Plevy, SE, Poe, JC, and Tedder, TF. "Peritoneal cavity regulatory B cells (B10 cells) modulate IFN-γ+CD4+ T cell numbers during colitis development in mice." J Immunol 191.5 (September 1, 2013): 2780-2795.
PMID
23918988
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
191
Issue
5
Publish Date
2013
Start Page
2780
End Page
2795
DOI
10.4049/jimmunol.1300649

Regulatory B cell (B10 Cell) expansion during Listeria infection governs innate and cellular immune responses in mice.

Pathogens use numerous methods to subvert host immune responses, including the modulation of host IL-10 production by diverse cell types. However, the B cell sources of IL-10 and their overall influence on innate and cellular immune responses have not been well characterized during infections. Using Listeria as a model pathogen, infection drove the acute expansion of a small subset of regulatory B cells (B10 cells) that potently suppress inflammation and autoimmunity through the production of IL-10. Unexpectedly, spleen bacteria loads were 92-97% lower in B10 cell-deficient CD19(-/-) mice, in mice depleted of mature B cells, and in mice treated with CD22 mAb to preferentially deplete B10 cells before infection. By contrast, the adoptive transfer of wild-type B10 cells reduced bacterial clearance by 38-fold in CD19(-/-) mice through IL-10-dependent pathways. B10 cell depletion using CD22 mAb significantly enhanced macrophage phagocytosis of Listeria and their production of IFN-γ, TNF-α, and NO ex vivo. Accelerated bacteria clearance following B10 cell depletion significantly reduced Ag-specific CD4(+) T cell proliferation and cytokine production, but did not alter CD8(+) T cell responses. B10 cell regulatory function during innate immune responses was nonetheless dependent on cognate interactions with CD4(+) T cells because B10 cells deficient in IL-10, MHC-II, or IL-21R expression did not influence Listeria clearance. Thus, Listeria manipulates immune responses through a strategy of immune evasion that involves the preferential expansion of endogenous B10 cells that regulate the magnitude and duration of both innate and cellular immune responses.

Authors
Horikawa, M; Weimer, ET; DiLillo, DJ; Venturi, GM; Spolski, R; Leonard, WJ; Heise, MT; Tedder, TF
MLA Citation
Horikawa, M, Weimer, ET, DiLillo, DJ, Venturi, GM, Spolski, R, Leonard, WJ, Heise, MT, and Tedder, TF. "Regulatory B cell (B10 Cell) expansion during Listeria infection governs innate and cellular immune responses in mice." J Immunol 190.3 (February 1, 2013): 1158-1168.
PMID
23275601
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
190
Issue
3
Publish Date
2013
Start Page
1158
End Page
1168
DOI
10.4049/jimmunol.1201427

Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function.

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.

Authors
DiLillo, DJ; Weinberg, JB; Yoshizaki, A; Horikawa, M; Bryant, JM; Iwata, Y; Matsushita, T; Matta, KM; Chen, Y; Venturi, GM; Russo, G; Gockerman, JP; Moore, JO; Diehl, LF; Volkheimer, AD; Friedman, DR; Lanasa, MC; Hall, RP; Tedder, TF
MLA Citation
DiLillo, DJ, Weinberg, JB, Yoshizaki, A, Horikawa, M, Bryant, JM, Iwata, Y, Matsushita, T, Matta, KM, Chen, Y, Venturi, GM, Russo, G, Gockerman, JP, Moore, JO, Diehl, LF, Volkheimer, AD, Friedman, DR, Lanasa, MC, Hall, RP, and Tedder, TF. "Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function." Leukemia 27.1 (January 2013): 170-182.
PMID
22713648
Source
pubmed
Published In
Leukemia
Volume
27
Issue
1
Publish Date
2013
Start Page
170
End Page
182
DOI
10.1038/leu.2012.165

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease.

B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of co-stimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of regulatory B cells has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported, with IL-10 being the most studied. In this review, this specific IL-10-producing subset of regulatory B cells has been labeled B10 cells to highlight that the regulatory function of these rare B cells is mediated by IL-10, and to distinguish them from other B cell subsets that regulate immune responses through different mechanisms. B10 cells are a functionally defined subset currently identified only by their competency to produce and secrete IL-10 following appropriate stimulation. Although B10 cells share surface markers with other previously defined B cell subsets, currently there is no cell surface or intracellular phenotypic marker or set of markers unique to B10 cells. The recent discovery of an effective way to expand B10 cells ex vivo opens new horizons in the potential therapeutic applications of this rare B cell subset. This review highlights the current knowledge on B10 cells and discusses their potential as novel therapeutic agents in autoimmunity.

Authors
Kalampokis, I; Yoshizaki, A; Tedder, TF
MLA Citation
Kalampokis, I, Yoshizaki, A, and Tedder, TF. "IL-10-producing regulatory B cells (B10 cells) in autoimmune disease." Arthritis Res Ther 15 Suppl 1 (2013): S1-. (Review)
PMID
23566714
Source
pubmed
Published In
Arthritis Research and Therapy
Volume
15 Suppl 1
Publish Date
2013
Start Page
S1
DOI
10.1186/ar3907

Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5 + CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV H mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice. © 2013 Macmillan Publishers Limited All rights reserved.

Authors
Dilillo, DJ; Weinberg, JB; Yoshizaki, A; Horikawa, M; Bryant, JM; Iwata, Y; Matsushita, T; Matta, KM; Chen, Y; Venturi, GM; Russo, G; Gockerman, JP; Moore, JO; Diehl, LF; Volkheimer, AD; Friedman, DR; Lanasa, MC; Hall, RP; Tedder, TF
MLA Citation
Dilillo, DJ, Weinberg, JB, Yoshizaki, A, Horikawa, M, Bryant, JM, Iwata, Y, Matsushita, T, Matta, KM, Chen, Y, Venturi, GM, Russo, G, Gockerman, JP, Moore, JO, Diehl, LF, Volkheimer, AD, Friedman, DR, Lanasa, MC, Hall, RP, and Tedder, TF. "Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function." Leukemia 27.1 (2013): 170-182.
Source
scival
Published In
Leukemia
Volume
27
Issue
1
Publish Date
2013
Start Page
170
End Page
182
DOI
10.1038/leu.2012.165

CD19 expression in B cells regulates atopic dermatitis in a mouse model

Atopic dermatitis is an inflammatory cutaneous disorder characterized by dry skin and relapsing eczematous skin lesions. Besides antibody production, the contribution of B cells to the pathogenesis of atopic dermatitis is unclear. In mice, repeated epicutaneous sensitization with ovalbumin induces inflamed skin lesions resembling human atopic dermatitis and therefore serves as an experimental model for this condition. To investigate the role of B cells in a murine model of atopic dermatitis, ovalbumin-sensitized allergic skin inflammation was assessed in mice lacking CD19. In ovalbumin-sensitized skin from CD19-deficient mice, the number of eosinophils and CD4+ T cells was reduced, and both epidermal and dermal thickening were decreased. Following in vitro stimulation with ovalbumin, CD19 deficiency significantly reduced the proliferation of CD4+, but not CD8+, T cells from spleen and draining lymph nodes. Furthermore, splenocytes and draining lymph node cells from ovalbumin-sensitized CD19-deficient mice secreted significantly less IL-4, IL-13, and IL-17 than ovalbumin-sensitized wild-type mice. These results suggest that CD19 expression in B cells plays a critical role in antigen-specific CD4+ T-cell proliferation and T helper 2 and 17 responses in a murine model of atopic dermatitis. Furthermore, the present findings may have implications for B-cell-targeted therapies for the treatment of atopic dermatitis. Copyright © 2013 American Society for Investigative Pathology.

Authors
Yanaba, K; Kamata, M; Asano, Y; Tada, Y; Sugaya, M; Kadono, T; Tedder, TF; Sato, S
MLA Citation
Yanaba, K, Kamata, M, Asano, Y, Tada, Y, Sugaya, M, Kadono, T, Tedder, TF, and Sato, S. "CD19 expression in B cells regulates atopic dermatitis in a mouse model." American Journal of Pathology 182.6 (2013): 2214-2222.
PMID
23583649
Source
scival
Published In
The American journal of pathology
Volume
182
Issue
6
Publish Date
2013
Start Page
2214
End Page
2222
DOI
10.1016/j.ajpath.2013.02.042

Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is an increasingly frequent cause of morbidity and mortality of allogeneic hematopoietic stem-cell transplantation. Sclerodermatous cGVHD (Scl-cGVHD) is characterized by fibrosis and autoimmune features resembling those of systemic sclerosis (SSc). Transplantation of B10.D2 bone marrow and splenocytes into irradiated BALB/c mice is an established model of human Scl-cGVHD. To examine the role of B cells in Scl-cGVHD, CD19-deficient (CD19(-/-)) mice were used as donors or recipients. CD19(-/-) donors induced more severe Scl-cGVHD than wild-type donors, but use of CD19(-/-) recipients resulted in no significant differences compared with wild-type recipients. Moreover, CD19 deficiency on donor B cells resulted in the expansion of splenic interleukin (IL) -6-producing monocytes/macrophages, cytotoxic CD8(+) T cells, and Th1 cells during the early stage of disease and increased the infiltration of T cells, TGF-β-producing monocytes/macrophages, and Th2 cells into the skin in the later stage of Scl-cGVHD. IL-10-producing regulatory B cells (B10 cells) were not reconstituted by CD19(-/-) donor cells, and early adoptive transfer of B10 cells attenuated the augmented manifestations of CD19(-/-) donor-induced Scl-cGVHD. Therefore, donor-derived B10 cells have a suppressive role in Scl-cGVHD development, warranting future investigation of regulatory B-cell-based therapy for treatment of Scl-cGVHD and SSc.

Authors
Huu, DL; Matsushita, T; Jin, G; Hamaguchi, Y; Hasegawa, M; Takehara, K; Tedder, TF; Fujimoto, M
MLA Citation
Huu, DL, Matsushita, T, Jin, G, Hamaguchi, Y, Hasegawa, M, Takehara, K, Tedder, TF, and Fujimoto, M. "Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease." Blood 121.16 (2013): 3274-3283.
PMID
23422748
Source
scival
Published In
Blood
Volume
121
Issue
16
Publish Date
2013
Start Page
3274
End Page
3283
DOI
10.1182/blood-2012-11-465658

Regulatory B cells suppress imiquimod-induced, psoriasis-like skin inflammation

Psoriasis is an inflammatory cutaneous disorder characterized by marked epidermal thickening and Th1 and Th17 cell infiltration. At present, the contribution of B cells to the pathogenesis of psoriasis is unclear. In mice, topical application of imiquimod induces inflamed skin lesions and serves as an experimental animal model for human psoriasis. In this study, we showed that imiquimod-induced skin inflammation was more severe in CD19-/- than WT mice. These inflammatory responses were negatively regulated by a unique IL-10-producing CD1dhiCD5+ regulatory B cell subset (B10 cells) that was absent in CD19-/- mice and represented only 1-2% of splenic B220+ cells in WT mice. Splenic B10 cells entered the circulation and migrated to draining LNs during imiquimod-induced skin inflammation, thereby suppressing IFN-γ and IL-17 production. Furthermore, adoptive transfer of these B10 cells from WT mice reduced inflammation in CD19-/- mice. The present findings provide direct evidence that B10 cells regulate imiquimod-induced skin inflammation and offer insights into regulatory B cell-based therapies for the treatment of psoriasis. © Society for Leukocyte Biology.

Authors
Yanaba, K; Kamata, M; Ishiura, N; Shibata, S; Asano, Y; Tada, Y; Sugaya, M; Kadono, T; Tedder, TF; Sato, S
MLA Citation
Yanaba, K, Kamata, M, Ishiura, N, Shibata, S, Asano, Y, Tada, Y, Sugaya, M, Kadono, T, Tedder, TF, and Sato, S. "Regulatory B cells suppress imiquimod-induced, psoriasis-like skin inflammation." Journal of Leukocyte Biology 94.4 (2013): 563-573.
PMID
23630391
Source
scival
Published In
Journal of leukocyte biology
Volume
94
Issue
4
Publish Date
2013
Start Page
563
End Page
573
DOI
10.1189/jlb.1112562

B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction

Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6Chi monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell-selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.

Authors
Zouggari, Y; Ait-Oufella, H; Bonnin, P; Simon, T; Sage, AP; Guérin, C; Vilar, J; Caligiuri, G; Tsiantoulas, D; Laurans, L; al, E
MLA Citation
Zouggari, Y, Ait-Oufella, H, Bonnin, P, Simon, T, Sage, AP, Guérin, C, Vilar, J, Caligiuri, G, Tsiantoulas, D, Laurans, L, and al, E. "B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction." Nature Medicine (2013).
PMID
24037091
Source
scival
Published In
Nature Medicine
Publish Date
2013
DOI
10.1038/nm.3284

Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions.

B cells regulate immune responses by producing antigen-specific antibodies. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.

Authors
Yoshizaki, A; Miyagaki, T; DiLillo, DJ; Matsushita, T; Horikawa, M; Kountikov, EI; Spolski, R; Poe, JC; Leonard, WJ; Tedder, TF
MLA Citation
Yoshizaki, A, Miyagaki, T, DiLillo, DJ, Matsushita, T, Horikawa, M, Kountikov, EI, Spolski, R, Poe, JC, Leonard, WJ, and Tedder, TF. "Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions." Nature 491.7423 (November 8, 2012): 264-268.
PMID
23064231
Source
pubmed
Published In
Nature
Volume
491
Issue
7423
Publish Date
2012
Start Page
264
End Page
268
DOI
10.1038/nature11501

Isolation and generation of human dendritic cells.

Dendritic cells are highly specialized antigen-presenting cells (APC), which may be isolated or generated from human blood mononuclear cells. Although mature blood dendritic cells normally represent ∼0.2% of human blood mononuclear cells, their frequency can be greatly increased using the cell enrichment methods described in this unit. More highly purified dendritic cell preparations can be obtained from these populations by sorting of fluorescence-labeled cells. Alternatively, dendritic cells can be generated from monocytes by culture with the appropriate cytokines, as described here. In addition, a negative selection approach is provided that may be employed to generate cell preparations that have been depleted of dendritic cells to be used for comparison in functional studies.

Authors
Nair, S; Archer, GE; Tedder, TF
MLA Citation
Nair, S, Archer, GE, and Tedder, TF. "Isolation and generation of human dendritic cells." Curr Protoc Immunol Chapter 7 (November 2012): Unit7.32-.
PMID
23129155
Source
pubmed
Published In
Current Protocols in Immunology
Volume
Chapter 7
Publish Date
2012
Start Page
Unit7.32
DOI
10.1002/0471142735.im0732s99

A c-Myc and surface CD19 signaling amplification loop promotes B cell lymphoma development and progression in mice.

Malignant B cells responding to external stimuli are likely to gain a growth advantage in vivo. These cells may therefore maintain surface CD19 expression to amplify transmembrane signals and promote their expansion and survival. To determine whether CD19 expression influences this process, Eμ-Myc transgenic (c-Myc(Tg)) mice that develop aggressive and lethal B cell lymphomas were made CD19 deficient (c-Myc(Tg)CD19⁻/⁻). Compared with c-Myc(Tg) and c-Myc(Tg)CD19⁺/⁻ littermates, the median life span of c-Myc(Tg)CD19⁻/⁻ mice was prolonged by 81-83% (p < 0.0001). c-Myc(Tg)CD19⁻/⁻ mice also lived 42% longer than c-Myc(Tg) littermates following lymphoma detection (p < 0.01). Tumor cells in c-Myc(Tg) and c-Myc(Tg)CD19⁻/⁻ mice were B lineage derived, had a similar phenotype with a large blastlike appearance, invaded multiple lymphoid tissues, and were lethal when adoptively transferred into normal recipient mice. Importantly, reduced lymphomagenesis in c-Myc(Tg)CD19⁻/⁻ mice was not due to reductions in early B cell numbers prior to disease onset. In mechanistic studies, constitutive c-Myc expression enhanced CD19 expression and phosphorylation on active sites. Reciprocally, CD19 expression in c-Myc(Tg) B cells enhanced c-Myc phosphorylation at regulatory sites, sustained higher c-Myc protein levels, and maintained a balance of cyclin D2 expression over that of cyclin D3. These findings define a new and novel c-Myc:CD19 regulatory loop that positively influences B cell transformation and lymphoma progression.

Authors
Poe, JC; Minard-Colin, V; Kountikov, EI; Haas, KM; Tedder, TF
MLA Citation
Poe, JC, Minard-Colin, V, Kountikov, EI, Haas, KM, and Tedder, TF. "A c-Myc and surface CD19 signaling amplification loop promotes B cell lymphoma development and progression in mice." J Immunol 189.5 (September 1, 2012): 2318-2325.
PMID
22826319
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
189
Issue
5
Publish Date
2012
Start Page
2318
End Page
2325
DOI
10.4049/jimmunol.1201000

CD22 and Siglec-G in B cell function and tolerance.

The immune system has evolved into two main arms: the primitive innate arm that is the first line of defense but relatively short-lived and broad acting; and the advanced adaptive arm that generates immunological memory, allowing rapid, specific recall responses. T cell-independent type-2 (TI-2) antigens (Ags) invoke innate immune responses. However, due to its 'at the ready' nature, how the innate arm of the immune system maintains tolerance to potentially abundant host TI-2 Ags remains elusive. Therefore, it is important to define the mechanisms that establish innate immune tolerance. This review highlights recent insights into B cell tolerance to theoretical self TI-2 Ags, and examines how the B cell-restricted sialic acid binding Ig-like lectins (Siglecs), CD22 and Siglec-G, might contribute to this process.

Authors
Poe, JC; Tedder, TF
MLA Citation
Poe, JC, and Tedder, TF. "CD22 and Siglec-G in B cell function and tolerance." Trends Immunol 33.8 (August 2012): 413-420. (Review)
PMID
22677186
Source
pubmed
Published In
Trends in Immunology
Volume
33
Issue
8
Publish Date
2012
Start Page
413
End Page
420
DOI
10.1016/j.it.2012.04.010

REGULATORY B10 CELLS DURING INFLAMMATION, AUTOIMMUNITY AND CANCER

Authors
Tedder, TF
MLA Citation
Tedder, TF. "REGULATORY B10 CELLS DURING INFLAMMATION, AUTOIMMUNITY AND CANCER." ANNALS OF THE RHEUMATIC DISEASES 71 (June 2012): 21-22.
Source
wos-lite
Published In
Annals of the rheumatic diseases
Volume
71
Publish Date
2012
Start Page
21
End Page
22

Regulatory B10 cells differentiate into antibody-secreting cells after transient IL-10 production in vivo.

Regulatory B cells that are functionally defined by their capacity to express IL-10 (B10 cells) downregulate inflammation and autoimmunity. In studies using well-defined IL-10 reporter mice, this rare B10 cell subset was also found to maintain a capacity for plasma cell differentiation. During a transient period of il10 transcription, the blimp1 and irf4 transcription factors were induced in B10 cells, whereas pax5 and bcl6 were downregulated as a significant fraction of B10 cells completed the genetic and phenotypic program leading to Ab-secreting cell differentiation in vitro and in vivo. B10 cell-derived IgM reacted with both self- and foreign Ags, whereas B10 cells generated Ag-specific IgG in response to immunizations. Moreover, B10 cells represented a significant source of serum IgM and IgG during adoptive-transfer experiments and produced Ag-specific, polyreactive and autoreactive Ab specificities that were consistent with their expression of a diverse AgR repertoire. Thereby, B10 cells limit inflammation and immune responses by the transient production of IL-10, and may facilitate clearance of their eliciting Ags through an inherent capacity to quickly generate polyreactive and/or Ag-specific Abs during humoral immune responses.

Authors
Maseda, D; Smith, SH; DiLillo, DJ; Bryant, JM; Candando, KM; Weaver, CT; Tedder, TF
MLA Citation
Maseda, D, Smith, SH, DiLillo, DJ, Bryant, JM, Candando, KM, Weaver, CT, and Tedder, TF. "Regulatory B10 cells differentiate into antibody-secreting cells after transient IL-10 production in vivo." J Immunol 188.3 (February 1, 2012): 1036-1048.
PMID
22198952
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
188
Issue
3
Publish Date
2012
Start Page
1036
End Page
1048
DOI
10.4049/jimmunol.1102500

Bone marrow dendritic cell-mediated regulation of TLR and B cell receptor signaling in B cells

Dendritic cells (DCs) play an essential role in regulation of immune responses. In the periphery, Ag presentation by DCs is critical for adaptive responses; for this reason, DCs are often targets of adjuvants that enhance vaccine responses. Activated mature DCs enhance B cell activation and differentiation by providing cytokines like BAFF and a proliferation-inducing ligand. However, the role of immature DCs in B cell tolerance is not well studied. Recently, mouse immature bone marrow-derived DCs (iBMDCs) have been shown to suppress anti-IgM-induced B cell activation. In this study, we tested the ability of mouse DCs to modulate B cell functions during TLR activation. We found that iBMDCs potently suppressed proliferation and differentiation of various B cell subsets on TLR stimulation. However, iBMDCs did not affect CD40-mediated B cell activation. Optimal suppression of B cell activation by iBMDCs required cell contact via the CD22 receptor on B cells. The B cell suppression was a property of iBMDCs or DCs resident in the bone marrow (BM), but not mature BM-derived DCs or DCs resident in the spleen. Presence of iBMDCs also enhanced the Ag-induced apoptotic response of BM B cells, suggesting that the suppressive effects of iBMDCs may have a role in B cell tolerance. Copyright © 2012 by The American Association of Immunologists, Inc.

Authors
Sindhava, VJ; Tuna, H; Gachuki, BW; DiLillo, DJ; Avdiushko, MG; Onami, TM; Tedder, TF; Cohen, DA; Bondada, S
MLA Citation
Sindhava, VJ, Tuna, H, Gachuki, BW, DiLillo, DJ, Avdiushko, MG, Onami, TM, Tedder, TF, Cohen, DA, and Bondada, S. "Bone marrow dendritic cell-mediated regulation of TLR and B cell receptor signaling in B cells." Journal of Immunology 189.7 (2012): 3355-3367.
PMID
22942427
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
189
Issue
7
Publish Date
2012
Start Page
3355
End Page
3367
DOI
10.4049/jimmunol.1101352

Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning

Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)-modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4+ and CD8+ T-cell subsets, autocrine IL-12 stimulation, and subsequent IFNγ secretion by the CAR+ T cells. Importantly, IL-12-secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell-mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients. © 2012 by The American Society of Hematology.

Authors
Pegram, HJ; Lee, JC; Hayman, EG; Imperato, GH; Tedder, TF; Sadelain, M; Brentjens, RJ
MLA Citation
Pegram, HJ, Lee, JC, Hayman, EG, Imperato, GH, Tedder, TF, Sadelain, M, and Brentjens, RJ. "Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning." Blood 119.18 (2012): 4133-4141.
PMID
22354001
Source
scival
Published In
Blood
Volume
119
Issue
18
Publish Date
2012
Start Page
4133
End Page
4141
DOI
10.1182/blood-2011-12-400044

CD22 serves as a receptor for soluble IgM

CD22 (Siglec-2) is a B-cell membrane-bound lectin that recognizes glycan ligands containing α2,6-linked sialic acid (α2,6Sia) and negatively regulates signaling through the B-cell Ag receptor (BCR). Although CD22 has been investigated extensively, its precise function remains unclear due to acting multiple phases. Here, we demonstrate that CD22 is efficiently activated in trans by complexes of Ag and soluble IgM (sIgM) due to the presence of glycan ligands on sIgM. This result strongly suggests sIgM as a natural trans ligand for CD22. Also, CD22 appears to serve as a receptor for sIgM, which induces a negative feedback loop for B-cell activation similar to the Fc receptor for IgG (FcγRIIB). © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Authors
Adachi, T; Harumiya, S; Takematsu, H; Kozutsumi, Y; Wabl, M; Fujimoto, M; Tedder, TF
MLA Citation
Adachi, T, Harumiya, S, Takematsu, H, Kozutsumi, Y, Wabl, M, Fujimoto, M, and Tedder, TF. "CD22 serves as a receptor for soluble IgM." European Journal of Immunology 42.1 (2012): 241-247.
PMID
21956693
Source
scival
Published In
European Journal of Immunology
Volume
42
Issue
1
Publish Date
2012
Start Page
241
End Page
247
DOI
10.1002/eji.201141899

Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice.

Current therapies for non-Hodgkin lymphoma commonly include CD20 mAb to deplete tumor cells. However, the response is not durable in a substantial proportion of patients. Herein, we report our studies in mice testing the hypothesis that heterogeneity in endogenous tissue CD20+ B cell depletion influences in vivo lymphoma therapy. Using highly effective CD20 mAbs that efficiently deplete endogenous mature B cells and homologous CD20+ primary lymphoma cells through monocyte- and antibody-dependent mechanisms, we found that lymphoma depletion and survival were reduced when endogenous host B cells were not depleted, particularly a rare IL-10-producing B cell subset (B10 cells) known to regulate inflammation and autoimmunity. Even small numbers of adoptively transferred B10 cells dramatically suppressed CD20 mAb-mediated lymphoma depletion by inhibiting mAb-mediated monocyte activation and effector function through IL-10-dependent mechanisms. However, the activation of innate effector cells using a TLR3 agonist that did not activate B10 cells overcame the negative regulatory effects of endogenous B10 cells and enhanced lymphoma depletion during CD20 immunotherapy in vivo. Thus, we conclude that endogenous B10 cells are potent negative regulators of innate immunity, with even small numbers of residual B10 cells able to inhibit lymphoma depletion by CD20 mAbs. Consequently, B10 cell removal could provide a way to optimize CD20 mAb-mediated clearance of malignant B cells in patients with non-Hodgkin lymphoma.

Authors
Horikawa, M; Minard-Colin, V; Matsushita, T; Tedder, TF
MLA Citation
Horikawa, M, Minard-Colin, V, Matsushita, T, and Tedder, TF. "Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice." J Clin Invest 121.11 (November 2011): 4268-4280.
PMID
22019587
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
121
Issue
11
Publish Date
2011
Start Page
4268
End Page
4280
DOI
10.1172/JCI59266

B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies.

Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

Authors
Winer, DA; Winer, S; Shen, L; Wadia, PP; Yantha, J; Paltser, G; Tsui, H; Wu, P; Davidson, MG; Alonso, MN; Leong, HX; Glassford, A; Caimol, M; Kenkel, JA; Tedder, TF; McLaughlin, T; Miklos, DB; Dosch, H-M; Engleman, EG
MLA Citation
Winer, DA, Winer, S, Shen, L, Wadia, PP, Yantha, J, Paltser, G, Tsui, H, Wu, P, Davidson, MG, Alonso, MN, Leong, HX, Glassford, A, Caimol, M, Kenkel, JA, Tedder, TF, McLaughlin, T, Miklos, DB, Dosch, H-M, and Engleman, EG. "B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies." Nat Med 17.5 (May 2011): 610-617.
PMID
21499269
Source
pubmed
Published In
Nature Medicine
Volume
17
Issue
5
Publish Date
2011
Start Page
610
End Page
617
DOI
10.1038/nm.2353

B-lymphocyte effector functions in health and disease.

B-lymphocytes have traditionally been thought to contribute to immunity and autoimmune disease through terminal differentiation into plasma cells that secrete antibody. However, studies in mice and recent clinical studies have demonstrated that genetically altered B-cell function and B-cell-targeted therapies can significantly affect autoimmune diseases that were predominantly thought to be T-cell-mediated. B-cell depletion in mouse models of disease has also led to the identification of alternative B-cell effector functions that regulate normal immune responses and autoimmune disease. This review highlights multiple B-cell effector mechanisms, including the promotion of cellular immunity, the negative regulation of immune responses, and the production of pathogenic antibodies.

Authors
DiLillo, DJ; Horikawa, M; Tedder, TF
MLA Citation
DiLillo, DJ, Horikawa, M, and Tedder, TF. "B-lymphocyte effector functions in health and disease." Immunol Res 49.1-3 (April 2011): 281-292. (Review)
Website
http://hdl.handle.net/10161/3077
PMID
21125343
Source
pubmed
Published In
Immunologic Research
Volume
49
Issue
1-3
Publish Date
2011
Start Page
281
End Page
292
DOI
10.1007/s12026-010-8189-3

CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies.

Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. CD137 is a costimulatory molecule expressed on a variety of immune cells after activation, including NK cells. In the present study, we show that an anti-CD137 agonistic mAb enhances the antilymphoma activity of rituximab by enhancing ADCC. Human NK cells up-regulate CD137 after encountering rituximab-coated tumor B cells, and subsequent stimulation of these NK cells with anti-CD137 mAb enhances rituximab-dependent cytotoxicity against the lymphoma cells. In a syngeneic murine lymphoma model and in a xenotransplanted human lymphoma model, sequential administration of anti-CD20 mAb followed by anti-CD137 mAb had potent antilymphoma activity in vivo. These results support a novel, sequential antibody approach against B-cell malignancies by targeting first the tumor and then the host immune system.

Authors
Kohrt, HE; Houot, R; Goldstein, MJ; Weiskopf, K; Alizadeh, AA; Brody, J; Müller, A; Pachynski, R; Czerwinski, D; Coutre, S; Chao, MP; Chen, L; Tedder, TF; Levy, R
MLA Citation
Kohrt, HE, Houot, R, Goldstein, MJ, Weiskopf, K, Alizadeh, AA, Brody, J, Müller, A, Pachynski, R, Czerwinski, D, Coutre, S, Chao, MP, Chen, L, Tedder, TF, and Levy, R. "CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies." Blood 117.8 (February 24, 2011): 2423-2432.
PMID
21193697
Source
pubmed
Published In
Blood
Volume
117
Issue
8
Publish Date
2011
Start Page
2423
End Page
2432
DOI
10.1182/blood-2010-08-301945

IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology.

Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases.

Authors
Pellegrini, M; Calzascia, T; Toe, JG; Preston, SP; Lin, AE; Elford, AR; Shahinian, A; Lang, PA; Lang, KS; Morre, M; Assouline, B; Lahl, K; Sparwasser, T; Tedder, TF; Paik, J-H; DePinho, RA; Basta, S; Ohashi, PS; Mak, TW
MLA Citation
Pellegrini, M, Calzascia, T, Toe, JG, Preston, SP, Lin, AE, Elford, AR, Shahinian, A, Lang, PA, Lang, KS, Morre, M, Assouline, B, Lahl, K, Sparwasser, T, Tedder, TF, Paik, J-H, DePinho, RA, Basta, S, Ohashi, PS, and Mak, TW. "IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology." Cell 144.4 (February 18, 2011): 601-613.
PMID
21295337
Source
pubmed
Published In
Cell
Volume
144
Issue
4
Publish Date
2011
Start Page
601
End Page
613
DOI
10.1016/j.cell.2011.01.011

B lymphocytes differentially influence acute and chronic allograft rejection in mice.

The relative contributions of B lymphocytes and plasma cells during allograft rejection remain unclear. Therefore, the effects of B cell depletion on acute cardiac rejection, chronic renal rejection, and skin graft rejection were compared using CD20 or CD19 mAbs. Both CD20 and CD19 mAbs effectively depleted mature B cells, and CD19 mAb treatment depleted plasmablasts and some plasma cells. B cell depletion did not affect acute cardiac allograft rejection, although CD19 mAb treatment prevented allograft-specific IgG production. Strikingly, CD19 mAb treatment significantly reduced renal allograft rejection and abrogated allograft-specific IgG development, whereas CD20 mAb treatment did not. By contrast, B cell depletion exacerbated skin allograft rejection and augmented the proliferation of adoptively transferred alloantigen-specific CD4(+) T cells, demonstrating that B cells can also negatively regulate allograft rejection. Thereby, B cells can either positively or negatively regulate allograft rejection depending on the nature of the allograft and the intensity of the rejection response. Moreover, CD19 mAb may represent a new approach for depleting both B cells and plasma cells to concomitantly impair T cell activation, inhibit the generation of new allograft-specific Abs, or reduce preexisting allograft-specific Ab levels in transplant patients.

Authors
DiLillo, DJ; Griffiths, R; Seshan, SV; Magro, CM; Ruiz, P; Coffman, TM; Tedder, TF
MLA Citation
DiLillo, DJ, Griffiths, R, Seshan, SV, Magro, CM, Ruiz, P, Coffman, TM, and Tedder, TF. "B lymphocytes differentially influence acute and chronic allograft rejection in mice." J Immunol 186.4 (February 15, 2011): 2643-2654.
PMID
21248259
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
186
Issue
4
Publish Date
2011
Start Page
2643
End Page
2654
DOI
10.4049/jimmunol.1002983

IL-10-producing regulatory B10 cells inhibit intestinal injury in a mouse model.

B cells mediate multiple functions that influence immune and inflammatory responses. In mice, the addition of dextran sulfate sodium (DSS) to drinking water leads to immediate intestinal injury. Dextran sulfate sodium-induced intestinal injury serves as an experimental animal model for human ulcerative colitis. The contribution of B cells to DSS-induced intestinal injury is unclear. In this study, we show that DSS-induced intestinal injury was more severe in CD19-deficient (CD19(-/-)) mice than in wild-type mice. These inflammatory responses were negatively regulated by a unique IL-10-producing CD1d(hi)CD5(+) regulatory B cell subset (B10 cells) that was absent in CD19(-/-) mice and represented only 1% to 2% of splenic B220(+) cells in wild-type mice. Remarkably, adoptive transfer of these B10 cells from wild-type mice reduced inflammation in CD19(-/-) mice in an IL-10-dependent manner. These results demonstrate that IL-10 production from regulatory B10 cells regulates DSS-induced intestinal injury. These findings may provide new insights and therapeutic approaches for treating ulcerative colitis.

Authors
Yanaba, K; Yoshizaki, A; Asano, Y; Kadono, T; Tedder, TF; Sato, S
MLA Citation
Yanaba, K, Yoshizaki, A, Asano, Y, Kadono, T, Tedder, TF, and Sato, S. "IL-10-producing regulatory B10 cells inhibit intestinal injury in a mouse model." Am J Pathol 178.2 (February 2011): 735-743.
PMID
21281806
Source
pubmed
Published In
The American journal of pathology
Volume
178
Issue
2
Publish Date
2011
Start Page
735
End Page
743
DOI
10.1016/j.ajpath.2010.10.022

Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells.

Regulatory B cells control inflammation and autoimmunity in mice, including the recently identified IL-10-competent B10 cell subset that represents 1% to 3% of spleen B cells. In this study, a comparable IL-10-competent B10 cell subset was characterized in human blood. B10 cells were functionally identified by their ability to express cytoplasmic IL-10 after 5 hours of ex vivo stimulation, whereas progenitor B10 (B10pro) cells required 48 hours of in vitro stimulation before they acquired the ability to express IL-10. B10 and B10pro cells represented 0.6% and approximately 5% of blood B cells, respectively. Ex vivo B10 and B10pro cells were predominantly found within the CD24(hi)CD27(+) B-cell subpopulation that was able to negatively regulate monocyte cytokine production through IL-10-dependent pathways during in vitro functional assays. Blood B10 cells were present in 91 patients with rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, autoimmune vesiculobullous skin disease, or multiple sclerosis, and were expanded in some cases as occurs in mice with autoimmune disease. Mean B10 + B10pro-cell frequencies were also significantly higher in patients with autoimmune disease compared with healthy controls. The characterization of human B10 cells will facilitate their identification and the study of their regulatory activities during human disease.

Authors
Iwata, Y; Matsushita, T; Horikawa, M; Dilillo, DJ; Yanaba, K; Venturi, GM; Szabolcs, PM; Bernstein, SH; Magro, CM; Williams, AD; Hall, RP; St Clair, EW; Tedder, TF
MLA Citation
Iwata, Y, Matsushita, T, Horikawa, M, Dilillo, DJ, Yanaba, K, Venturi, GM, Szabolcs, PM, Bernstein, SH, Magro, CM, Williams, AD, Hall, RP, St Clair, EW, and Tedder, TF. "Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells." Blood 117.2 (January 13, 2011): 530-541.
PMID
20962324
Source
pubmed
Published In
Blood
Volume
117
Issue
2
Publish Date
2011
Start Page
530
End Page
541
DOI
10.1182/blood-2010-07-294249

Identifying regulatory B cells (B10 cells) that produce IL-10 in mice.

Regulatory B cells that produce IL-10 are now recognized as an important component of the immune system. We have identified a rare antigen-specific regulatory B-cell subset with a unique CD1d(hi)CD5(+)CD19(hi) phenotype in the spleens of wild-type mice. We call these cells B10 cells because they are responsible for most B cell IL-10 production, they appear to only produce IL-10 after 5 h of in vitro stimulation, and to distinguish them from other potential regulatory B cell subsets. B10 progenitor (B10pro) cells have also been identified within the spleen CD1d(hi)CD5(+)CD19(hi) B-cell subset, and within other lymphoid tissues. Herein, four methods for identifying and isolating regulatory IL-10-producing B10 cells in mice are provided. The first two methods are used to identify and enumerate B10 and B10pro cells based on their cell surface phenotypes and cytoplasmic IL-10 staining. The last two methods are used to isolate viable B10 cells for adoptive transfer and functional studies. These methods should facilitate the study of B10 cells in inflammation, autoimmune disease, immune responses, and cancer therapy.

Authors
Matsushita, T; Tedder, TF
MLA Citation
Matsushita, T, and Tedder, TF. "Identifying regulatory B cells (B10 cells) that produce IL-10 in mice." Methods Mol Biol 677 (2011): 99-111.
PMID
20941605
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
677
Publish Date
2011
Start Page
99
End Page
111
DOI
10.1007/978-1-60761-869-0_7

Amplified B lymphocyte CD40 signaling drives regulatory B10 cell expansion in mice.

BACKGROUND: Aberrant CD40 ligand (CD154) expression occurs on both T cells and B cells in human lupus patients, which is suggested to enhance B cell CD40 signaling and play a role in disease pathogenesis. Transgenic mice expressing CD154 by their B cells (CD154(TG)) have an expanded spleen B cell pool and produce autoantibodies (autoAbs). CD22 deficient (CD22(-/-)) mice also produce autoAbs, and importantly, their B cells are hyper-proliferative following CD40 stimulation ex vivo. Combining these 2 genetic alterations in CD154(TG)CD22(-/-) mice was thereby predicted to intensify CD40 signaling and autoimmune disease due to autoreactive B cell expansion and/or activation. METHODOLOGY/PRINCIPAL FINDINGS: CD154(TG)CD22(-/-) mice were assessed for their humoral immune responses and for changes in their endogenous lymphocyte subsets. Remarkably, CD154(TG)CD22(-/-) mice were not autoimmune, but instead generated minimal IgG responses against both self and foreign antigens. This paucity in IgG isotype switching occurred despite an expanded spleen B cell pool, higher serum IgM levels, and augmented ex vivo B cell proliferation. Impaired IgG responses in CD154(TG)CD22(-/-) mice were explained by a 16-fold expansion of functional, mature IL-10-competent regulatory spleen B cells (B10 cells: 26.7×10(6)±6 in CD154(TG)CD22(-/-) mice; 1.7×10(6)±0.4 in wild type mice, p<0.01), and an 11-fold expansion of B10 cells combined with their ex vivo-matured progenitors (B10+B10pro cells: 66×10(6)±3 in CD154(TG)CD22(-/-) mice; 6.1×10(6)±2 in wild type mice, p<0.01) that represented 39% of all spleen B cells. CONCLUSIONS/SIGNIFICANCE: These results demonstrate for the first time that the IL-10-producing B10 B cell subset has the capacity to suppress IgG humoral immune responses against both foreign and self antigens. Thereby, therapeutic agents that drive regulatory B10 cell expansion in vivo may inhibit pathogenic IgG autoAb production in humans.

Authors
Poe, JC; Smith, SH; Haas, KM; Yanaba, K; Tsubata, T; Matsushita, T; Tedder, TF
MLA Citation
Poe, JC, Smith, SH, Haas, KM, Yanaba, K, Tsubata, T, Matsushita, T, and Tedder, TF. "Amplified B lymphocyte CD40 signaling drives regulatory B10 cell expansion in mice." PLoS One 6.7 (2011): e22464-.
PMID
21799861
Source
pubmed
Published In
PloS one
Volume
6
Issue
7
Publish Date
2011
Start Page
e22464
DOI
10.1371/journal.pone.0022464

Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants

Memory B cells (MBCs) and long-lived plasma cells (LLPCs) persist after clearance of infection, yet the specific and nonredundant role MBCs play in subsequent protection is unclear. After resolution of West Nile virus infection in mice, we demonstrate that LLPCs were specific for a single dominant neutralizing epitope, such that immune serum poorly inhibited a variant virus that encoded a mutation at this critical epitope. In contrast, a large fraction of MBC produced antibody that recognized both wild-type (WT) and mutant viral epitopes. Accordingly, antibody produced by the polyclonal pool of MBC neutralized WT and variant viruses equivalently. Remarkably, we also identified MBC clones that recognized the mutant epitope better than the WT protein, despite never having been exposed to the variant virus. The ability of MBCs to respond to variant viruses in vivo was confirmed by experiments in which MBCs were adoptively transferred or depleted before secondary challenge. Our data demonstrate that class-switched MBC can respond to variants of the original pathogen that escape neutralization of antibody produced by LLPC without a requirement for accumulating additional somatic mutations. © 2011 Purtha et al.

Authors
Purtha, WE; Tedder, TF; Johnson, S; Bhattacharya, D; Diamond, MS
MLA Citation
Purtha, WE, Tedder, TF, Johnson, S, Bhattacharya, D, and Diamond, MS. "Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants." Journal of Experimental Medicine 208.13 (2011): 2599-2606.
PMID
22162833
Source
scival
Published In
The Journal of Experimental Medicine
Volume
208
Issue
13
Publish Date
2011
Start Page
2599
End Page
2606
DOI
10.1084/jem.20110740

A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo

Human cluster of differentiation (CD) antigen 19 is a B cell-specific surface antigen and an attractive target for therapeutic monoclonal antibody (mAb) approaches to treat malignancies of B cell origin. MEDI-551 is an affinity-optimized and afucosylated CD19 mAb with enhanced antibody-dependent cellular cytotoxicity (ADCC). The results from in vitro ADCC assays with Natural Killer cells as effector cells, demonstrate that MEDI-551 is effective at lower mAb doses than rituximab with multiple cell lines as well as primary chronic lymphocytic leukaemia and acute lymphoblastic leukaemia samples. Targeting CD19 with MEDI-551 was also effective in several severe combined immunodeficiency lymphoma models. Furthermore, the combination of MEDI-551 with rituximab resulted in prolonged suppression of tumour growth, demonstrating that therapeutic mAbs with overlapping effector function can be combined for greater tumour growth inhibition. Together, the data demonstrate that MEDI-551 has potent antitumour activity in preclinical models of B cell malignancies. The results also suggest that the combination of the ADCC-enhanced CD19 mAb with an anti-CD20 mAb could be a novel approach for the treatment of B cell lymphomas. © 2011 Blackwell Publishing Ltd.

Authors
Ward, E; Mittereder, N; Kuta, E; Sims, GP; Bowen, MA; Dall'Acqua, W; Tedder, T; Kiener, P; Coyle, AJ; Wu, H; Jallal, B; Herbst, R
MLA Citation
Ward, E, Mittereder, N, Kuta, E, Sims, GP, Bowen, MA, Dall'Acqua, W, Tedder, T, Kiener, P, Coyle, AJ, Wu, H, Jallal, B, and Herbst, R. "A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo." British Journal of Haematology 155.4 (2011): 426-437.
PMID
21902688
Source
scival
Published In
British Journal of Haematology
Volume
155
Issue
4
Publish Date
2011
Start Page
426
End Page
437
DOI
10.1111/j.1365-2141.2011.08857.x

B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies

Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

Authors
Winer, DA; Winer, S; Shen, L; Wadia, PP; Yantha, J; Paltser, G; Tsui, H; Wu, P; Davidson, MG; Alonso, MN; Leong, HX; Glassford, A; Caimol, M; Kenkel, JA; Tedder, TF; McLaughlin, T; Miklos, DB; Dosch, H-M; Engleman, EG
MLA Citation
Winer, DA, Winer, S, Shen, L, Wadia, PP, Yantha, J, Paltser, G, Tsui, H, Wu, P, Davidson, MG, Alonso, MN, Leong, HX, Glassford, A, Caimol, M, Kenkel, JA, Tedder, TF, McLaughlin, T, Miklos, DB, Dosch, H-M, and Engleman, EG. "B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies." Nature Medicine (2011).
Source
scival
Published In
Nature Medicine
Publish Date
2011
DOI
10.1038/nm.2353

α4β7 Integrin is essential for contact hypersensitivity by regulating migration of T cells to skin.

BACKGROUND: β7 Integrin, a cell adhesion molecule, is present in the form of α4β7 integrin or αEβ7 integrin. α4β7 Integrin is expressed on most leucocytes and is essential for their migration to gut-associated lymphoid tissues by interacting with its primary ligand, mucosal addressin cell adhesion molecule-1, which is preferentially expressed in gut-associated lymphoid tissues. Although the importance of α4β7 integrin in intestinal inflammation has been established, its role in cutaneous inflammation remains to be elucidated. OBJECTIVE: We sought to investigate the role of β7 integrin in cutaneous inflammation. METHODS: We used a murine contact hypersensitivity model and examined the role of β7 integrin by using β7 integrin-deficient and αE integrin-deficient mice. RESULTS: β7 Integrin-deficient mice, not αE integrin-deficient mice, are defective in contact hypersensitivity responses. β7 Integrin deficiency does not affect irritant contact dermatitis. The distribution, migration, and function of antigen presenting cells from β7 integrin-deficient mice are comparable to those from wild-type mice. Moreover, sensitized β7 integrin-deficient T cells are able to respond to antigen stimuli in vitro and elicit contact hypersensitivity responses when directly injected into the skin. However, they are defective in reaching the skin under inflammatory conditions, resulting in reduced contact hypersensitivity responses when intravenously injected. Furthermore, intraperitoneal injection of anti-α4β7 integrin neutralizing antibody elicit impaired contact hypersensitivity responses. CONCLUSION: α4β7 Integrin contributes to contact hypersensitivity responses by regulating T-cell migration to inflammatory skin.

Authors
Ohmatsu, H; Kadono, T; Sugaya, M; Tomita, M; Kai, H; Miyagaki, T; Saeki, H; Tamaki, K; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Ohmatsu, H, Kadono, T, Sugaya, M, Tomita, M, Kai, H, Miyagaki, T, Saeki, H, Tamaki, K, Steeber, DA, Tedder, TF, and Sato, S. "α4β7 Integrin is essential for contact hypersensitivity by regulating migration of T cells to skin." J Allergy Clin Immunol 126.6 (December 2010): 1267-1276.
PMID
21047673
Source
pubmed
Published In
Journal of Allergy and Clinical Immunology
Volume
126
Issue
6
Publish Date
2010
Start Page
1267
End Page
1276
DOI
10.1016/j.jaci.2010.08.048

L-selectin is dispensable for T regulatory cell function postallogeneic bone marrow transplantation.

In murine models, the adoptive transfer of CD4(+) /CD25(+) regulatory T cells (T(regs) ) inhibited graft-versus-host disease (GvHD). Previous work has indicated a critical role for the adhesion molecule L-selectin (CD62L) in the function of T(regs) in preventing GvHD. Here we examined the capacity of naive wild-type (WT), CD62L(-/-) and ex vivo expanded CD62L(Lo) T(regs) to inhibit acute GvHD. Surprisingly, we found that CD62L(-/-) T(regs) were potent suppressors of GvHD, whereas CD62L(Lo) T(regs) were unable to inhibit disease despite being functionally competent to suppress allo T cell responses in vitro. Concomitant with improved outcomes, WT and CD62L(-/-) T(regs) significantly reduced liver pathology and systemic pro-inflammatory cytokine production, although CD62L(-/-) T(regs) were less effective in reducing lung pathology. While accumulation of CD62L(-/-) T(regs) in GvHD target organs was equivalent to WT T(regs) , CD62L(-/-) T(regs) did not migrate as well as WT T(regs) to peripheral lymph nodes (PLNs) over the first 2 weeks posttransplantation. This work demonstrated that CD62L was dispensable for T(reg) -mediated protection from GvHD.

Authors
Carlson, MJ; Fulton, LM; Coghill, JM; West, ML; Burgents, JE; Wan, Y; Panoskaltsis-Mortari, A; Tedder, TF; Blazar, BR; Serody, JS
MLA Citation
Carlson, MJ, Fulton, LM, Coghill, JM, West, ML, Burgents, JE, Wan, Y, Panoskaltsis-Mortari, A, Tedder, TF, Blazar, BR, and Serody, JS. "L-selectin is dispensable for T regulatory cell function postallogeneic bone marrow transplantation." Am J Transplant 10.12 (December 2010): 2596-2603.
PMID
21070606
Source
pubmed
Published In
American Journal of Transplantation
Volume
10
Issue
12
Publish Date
2010
Start Page
2596
End Page
2603
DOI
10.1111/j.1600-6143.2010.03319.x

Mouse and human regulatory B10 cells control inflammation and autoimmunity

Authors
Tedder, TF
MLA Citation
Tedder, TF. "Mouse and human regulatory B10 cells control inflammation and autoimmunity." December 2010.
Source
wos-lite
Published In
Immunology
Volume
131
Publish Date
2010
Start Page
1
End Page
2

B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody.

The pan B-cell surface antigen CD19 is an attractive target for therapeutic monoclonal antibody (mAb) approaches. We have generated a new afucosylated anti-human (hu)CD19 mAb, MEDI-551, with increased affinity to human FcγRIIIA and mouse FcγRIV and enhanced antibody-dependent cellular cytotoxicity (ADCC). During in vitro ADCC assays with B-cell lines, MEDI-551 is effective at much lower mAb concentrations than the fucosylated parental mAb anti-CD19-2. Furthermore, the afucosylated CD19 mAb MEDI-551 depleted B cells from normal donor peripheral blood mononuclear cell samples in an autologous ADCC assay, as well as blood and tissue B cells in human CD19/CD20 double transgenic (Tg) mice at lower concentrations than that of the positive control mAb rituximab. In huCD19/CD20 Tg mice, both macrophage-mediated phagocytosis and complement-dependent cytotoxicity contribute to depletion with rituximab; MEDI-551 did not require complement for maximal B-cell depletion. Furthermore, extended B-cell depletion from the blood and spleen was achieved with MEDI-551, which is probably explained by bone marrow B-cell depletion in huCD19/CD20 Tg mice relative to the control mAb rituximab. In summary, MEDI-551 has potent B-cell-depleting activity in vitro and in vivo and may be a promising new approach for the treatment of B-cell malignancies and autoimmune diseases.

Authors
Herbst, R; Wang, Y; Gallagher, S; Mittereder, N; Kuta, E; Damschroder, M; Woods, R; Rowe, DC; Cheng, L; Cook, K; Evans, K; Sims, GP; Pfarr, DS; Bowen, MA; Dall'Acqua, W; Shlomchik, M; Tedder, TF; Kiener, P; Jallal, B; Wu, H; Coyle, AJ
MLA Citation
Herbst, R, Wang, Y, Gallagher, S, Mittereder, N, Kuta, E, Damschroder, M, Woods, R, Rowe, DC, Cheng, L, Cook, K, Evans, K, Sims, GP, Pfarr, DS, Bowen, MA, Dall'Acqua, W, Shlomchik, M, Tedder, TF, Kiener, P, Jallal, B, Wu, H, and Coyle, AJ. "B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody." J Pharmacol Exp Ther 335.1 (October 2010): 213-222.
PMID
20605905
Source
pubmed
Published In
The Journal of pharmacology and experimental therapeutics
Volume
335
Issue
1
Publish Date
2010
Start Page
213
End Page
222
DOI
10.1124/jpet.110.168062

Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model.

Mice s.c. injected with bleomycin, an experimental model for human systemic sclerosis, develop skin and lung fibrosis, which is mediated by inflammatory cell infiltration. This process is highly regulated by multiple adhesion molecules and does not require Ag sensitization. To assess the role of adhesion molecules in this pathogenetic process, bleomycin-induced fibrosis was examined in mice lacking adhesion molecules. L-selectin and/or ICAM-1 deficiency inhibited skin and lung fibrosis with decreased Th2 and Th17 cytokines and increased Th1 cytokines. In contrast, P-selectin deficiency, E-selectin deficiency with or without P-selectin blockade, or P-selectin glycoprotein ligand 1 (PSGL-1) deficiency augmented the fibrosis in parallel with increased Th2 and Th17 cytokines and decreased Th1 cytokines. Furthermore, loss of L-selectin and/or ICAM-1 reduced Th2 and Th17 cell numbers in bronchoalveolar lavage fluid, whereas loss of P-selectin, E-selectin, or PSGL-1 reduced Th1 cell numbers. Moreover, Th1 cells exhibited higher PSGL-1 expression and lower expression of LFA-1, a ligand for ICAM-1, whereas Th2 and Th17 cells showed higher LFA-1 and lower PSGL-1 expression. This study suggests that L-selectin and ICAM-1 regulate Th2 and Th17 cell accumulation into the skin and lung, leading to the development of fibrosis, and that P-selectin, E-selectin, and PSGL-1 regulate Th1 cell infiltration, resulting in the inhibition of fibrosis.

Authors
Yoshizaki, A; Yanaba, K; Iwata, Y; Komura, K; Ogawa, A; Akiyama, Y; Muroi, E; Hara, T; Ogawa, F; Takenaka, M; Shimizu, K; Hasegawa, M; Fujimoto, M; Tedder, TF; Sato, S
MLA Citation
Yoshizaki, A, Yanaba, K, Iwata, Y, Komura, K, Ogawa, A, Akiyama, Y, Muroi, E, Hara, T, Ogawa, F, Takenaka, M, Shimizu, K, Hasegawa, M, Fujimoto, M, Tedder, TF, and Sato, S. "Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model." J Immunol 185.4 (August 15, 2010): 2502-2515.
PMID
20624949
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
185
Issue
4
Publish Date
2010
Start Page
2502
End Page
2515
DOI
10.4049/jimmunol.0901778

Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis.

Experimental autoimmune encephalomyelitis (EAE) is a T lymphocyte-mediated autoimmune disease of the CNS. Significant roles for B cells and a rare IL-10-producing CD1d(high)CD5(+) regulatory B cell subset (B10 cells) have been identified during the initiation and progression of EAE. Whether and how the regulatory functions of B10 cells and FoxP3(+) T regulatory cells (Tregs) overlap or influence EAE immunopathogenesis independently has remained unanswered. This study demonstrates that the number of endogenous or adoptively transferred B10 cells directly influenced EAE pathogenesis through their production of IL-10. B10 cell numbers expanded quickly within the spleen, but not CNS following myelin oligodendrocyte glycoprotein(35-55) immunization, which paralleled B10 cell regulation of disease initiation. The adoptive transfer of myelin oligodendrocyte glycoprotein(33-35)-sensitized B10 cells into wild-type mice reduced EAE initiation dramatically. However, B10 cells did not suppress ongoing EAE disease. Rather, Treg numbers expanded significantly within the CNS during disease progression, which paralleled their negative regulation of late-phase disease. Likewise, the preferential depletion of B10 cells in vivo during disease initiation enhanced EAE pathogenesis, whereas Treg depletion enhanced late-phase disease. B10 cells did not regulate T cell proliferation during in vitro assays, but significantly altered CD4(+) T cell IFN-gamma and TNF-alpha production. Furthermore, B10 cells downregulated the ability of dendritic cells to act as APCs and thereby indirectly modulated T cell proliferation. Thus, B10 cells predominantly control disease initiation, whereas Tregs reciprocally inhibit late-phase disease, with overlapping B10 cell and Treg functions shaping the normal course of EAE immunopathogenesis.

Authors
Matsushita, T; Horikawa, M; Iwata, Y; Tedder, TF
MLA Citation
Matsushita, T, Horikawa, M, Iwata, Y, and Tedder, TF. "Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis." J Immunol 185.4 (August 15, 2010): 2240-2252.
PMID
20624940
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
185
Issue
4
Publish Date
2010
Start Page
2240
End Page
2252
DOI
10.4049/jimmunol.1001307

B cell depletion reduces the development of atherosclerosis in mice.

B cell depletion significantly reduces the burden of several immune-mediated diseases. However, B cell activation has been until now associated with a protection against atherosclerosis, suggesting that B cell-depleting therapies would enhance cardiovascular risk. We unexpectedly show that mature B cell depletion using a CD20-specific monoclonal antibody induces a significant reduction of atherosclerosis in various mouse models of the disease. This treatment preserves the production of natural and potentially protective anti-oxidized low-density lipoprotein (oxLDL) IgM autoantibodies over IgG type anti-oxLDL antibodies, and markedly reduces pathogenic T cell activation. B cell depletion diminished T cell-derived IFN-gamma secretion and enhanced production of IL-17; neutralization of the latter abrogated CD20 antibody-mediated atheroprotection. These results challenge the current paradigm that B cell activation plays an overall protective role in atherogenesis and identify new antiatherogenic strategies based on B cell modulation.

Authors
Ait-Oufella, H; Herbin, O; Bouaziz, J-D; Binder, CJ; Uyttenhove, C; Laurans, L; Taleb, S; Van Vré, E; Esposito, B; Vilar, J; Sirvent, J; Van Snick, J; Tedgui, A; Tedder, TF; Mallat, Z
MLA Citation
Ait-Oufella, H, Herbin, O, Bouaziz, J-D, Binder, CJ, Uyttenhove, C, Laurans, L, Taleb, S, Van Vré, E, Esposito, B, Vilar, J, Sirvent, J, Van Snick, J, Tedgui, A, Tedder, TF, and Mallat, Z. "B cell depletion reduces the development of atherosclerosis in mice." J Exp Med 207.8 (August 2, 2010): 1579-1587.
PMID
20603314
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
207
Issue
8
Publish Date
2010
Start Page
1579
End Page
1587
DOI
10.1084/jem.20100155

B-cell homeostasis requires complementary CD22 and BLyS/BR3 survival signals.

Peripheral B-cell numbers are tightly regulated by homeostatic mechanisms that influence the transitional and mature B-cell compartments and dictate the size and clonotypic diversity of the B-cell repertoire. B-lymphocyte stimulator (BLyS, a trademark of Human Genome Sciences, Inc.) plays a key role in regulating peripheral B-cell homeostasis. CD22 also promotes peripheral B-cell survival through ligand-dependent mechanisms. The B-cell subsets affected by the absence of BLyS and CD22 signals overlap, suggesting that BLyS- and CD22-mediated survival are intertwined. To examine this, the effects of BLyS insufficiency following neutralizing BLyS mAb treatment in mice also treated with CD22 ligand-blocking mAb were examined. Combined targeting of the BLyS and CD22 survival pathways led to significantly greater clearance of recirculating bone marrow, blood, marginal zone and follicular B cells than either treatment alone. Likewise, BLyS blockade further reduced bone marrow, blood and spleen B-cell numbers in CD22(-/-) mice. Notably, BLyS receptor expression and downstream signaling were normal in CD22(-/-) B cells, suggesting that CD22 does not directly alter BLyS responsiveness. CD22 survival signals were likewise intact in the absence of BLyS, as CD22 mAb treatment depleted blood B cells from mice with impaired BLyS receptor 3 (BR3) signaling. Finally, enforced BclxL expression, which rescues BR3 impairment, did not affect B-cell depletion following CD22 mAb treatment. Thus, the current studies support a model whereby CD22 and BLyS promote the survival of overlapping B-cell subsets but contribute to their maintenance through independent and complementary signaling pathways.

Authors
Smith, SH; Haas, KM; Poe, JC; Yanaba, K; Ward, CD; Migone, T-S; Tedder, TF
MLA Citation
Smith, SH, Haas, KM, Poe, JC, Yanaba, K, Ward, CD, Migone, T-S, and Tedder, TF. "B-cell homeostasis requires complementary CD22 and BLyS/BR3 survival signals." Int Immunol 22.8 (August 2010): 681-691.
PMID
20513733
Source
pubmed
Published In
International Immunology
Volume
22
Issue
8
Publish Date
2010
Start Page
681
End Page
691
DOI
10.1093/intimm/dxq055

The differential role of L-selectin and ICAM-1 in Th1-type and Th2-type contact hypersensitivity.

Sensitization and challenge using DNFB induce contact hypersensitivity (CHS) with predominant type 1 helper (Th1) cell infiltration, whereas those using FITC generate CHS with Th2 cell infiltration. CHS results from inflammatory cell infiltration, a process that is highly regulated by the expression of multiple adhesion molecules. We attempted to determine the role of L-selectin and ICAM-1 in Th1- and Th2-type CHS induced by DNFB or FITC in mice lacking either L-selectin, ICAM-1, or both. Th1-type CHS induced by DNFB was inhibited by L-selectin and/or ICAM-1 deficiency, which was associated with reduced IFN-gamma expression. Similarly, Th2-type CHS induced by FITC was inhibited by L-selectin deficiency. However, Th2-type CHS was increased by ICAM-1 deficiency and accompanied by increased Th2 cytokine expression. Infiltration of in vitro-generated Th1 cells into the FITC-challenged skin decreased in ICAM-1-deficient mice, whereas in vitro-generated Th2 cell infiltration increased, suggesting that ICAM-1 mediates Th1 cell migration and that in the absence of ICAM-1, Th1 cell recruitment decreased, whereas relative Th2 cell migration increased. These results suggest that ICAM-1 mediates Th1 cell recruitment irrespective of DNFB or FITC and that L-selectin recruits Th1 cells in Th1-type CHS, whereas it recruits Th2 cells in Th2-type CHS.

Authors
Ogawa, A; Yoshizaki, A; Yanaba, K; Ogawa, F; Hara, T; Muroi, E; Takenaka, M; Shimizu, K; Hasegawa, M; Fujimoto, M; Tedder, TF; Sato, S
MLA Citation
Ogawa, A, Yoshizaki, A, Yanaba, K, Ogawa, F, Hara, T, Muroi, E, Takenaka, M, Shimizu, K, Hasegawa, M, Fujimoto, M, Tedder, TF, and Sato, S. "The differential role of L-selectin and ICAM-1 in Th1-type and Th2-type contact hypersensitivity." J Invest Dermatol 130.6 (June 2010): 1558-1570.
PMID
20182448
Source
pubmed
Published In
Journal of Investigative Dermatology
Volume
130
Issue
6
Publish Date
2010
Start Page
1558
End Page
1570
DOI
10.1038/jid.2010.25

Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice.

Delineating the relative contributions of B lymphocytes during the course of autoimmune disease has been difficult. Therefore, the effects of depleting all mature B cells using a potent CD20 mAb, or of depleting circulating and marginal zone B cells using a ligand-blocking CD22 mAb, were compared in NZB/W F(1) mice, a model for human systemic lupus erythematosus. Single low-dose mAb treatments depleted B cells efficiently in both NZB/W F(1) and C57BL/6 mice. Prophylactic B cell depletion by repeated CD20 mAb treatments prolonged survival during pristane-accelerated lupus in NZB/W F(1) mice, whereas CD22 mAb had little effect. Despite effective B cell depletion, neither mAb treatment prevented autoantibody generation. In addition, CD20, CD22, and control mAb-treated NZB/W F(1) mice developed anti-mouse IgG autoantibodies in contrast to parental NZB and NZW strains, which may have reduced the effectiveness of B cell depletion. Despite this, low-dose CD20 mAb treatment initiated in 12-28-wk-old mice, and administered every 4 wk thereafter, significantly delayed spontaneous disease in NZB/W F(1) mice. By contrast, B cell depletion initiated in 4-wk-old mice hastened disease onset, which paralleled depletion of the IL-10-producing regulatory B cell subset called B10 cells. B10 cells were phenotypically similar in NZB/W F(1) and C57BL/6 mice, but were expanded significantly in young NZB/W F(1) mice. Thus, B cell depletion had significant effects on NZB/W F(1) mouse survival that were dependent on the timing of treatment initiation. Therefore, distinct B cell populations can have opposing protective and pathogenic roles during lupus progression.

Authors
Haas, KM; Watanabe, R; Matsushita, T; Nakashima, H; Ishiura, N; Okochi, H; Fujimoto, M; Tedder, TF
MLA Citation
Haas, KM, Watanabe, R, Matsushita, T, Nakashima, H, Ishiura, N, Okochi, H, Fujimoto, M, and Tedder, TF. "Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice." J Immunol 184.9 (May 1, 2010): 4789-4800.
PMID
20368280
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
184
Issue
9
Publish Date
2010
Start Page
4789
End Page
4800
DOI
10.4049/jimmunol.0902391

CD22 expression mediates the regulatory functions of peritoneal B-1a cells during the remission phase of contact hypersensitivity reactions.

Although contact hypersensitivity (CHS) has been considered a prototype of T cell-mediated immune reactions, recently a significant contribution of regulatory B cell subsets in the suppression of CHS has been demonstrated. CD22, one of the sialic acid-binding immunoglobulin-like lectins, is a B cell-specific molecule that negatively regulates BCR signaling. To clarify the roles of B cells in CHS, CHS in CD22(-/-) mice was investigated. CD22(-/-) mice showed delayed recovery from CHS reactions compared with that of wild-type mice. Transfer of wild-type peritoneal B-1a cells reversed the prolonged CHS reaction seen in CD22(-/-) mice, and this was blocked by the simultaneous injection with IL-10 receptor Ab. Although CD22(-/-) peritoneal B-1a cells were capable of producing IL-10 at wild-type levels, i.p. injection of differentially labeled wild-type/CD22(-/-) B cells demonstrated that a smaller number of CD22(-/-) B cells resided in lymphoid organs 5 d after CHS elicitation, suggesting a defect in survival or retention in activated CD22(-/-) peritoneal B-1 cells. Thus, our study reveals a regulatory role for peritoneal B-1a cells in CHS. Two distinct regulatory B cell subsets cooperatively inhibit CHS responses. Although splenic CD1d(hi)CD5(+) B cells have a crucial role in suppressing the acute exacerbating phase of CHS, peritoneal B-1a cells are likely to suppress the late remission phase as "regulatory B cells." CD22 deficiency results in disturbed CHS remission by impaired retention or survival of peritoneal B-1a cells that migrate into lymphoid organs.

Authors
Nakashima, H; Hamaguchi, Y; Watanabe, R; Ishiura, N; Kuwano, Y; Okochi, H; Takahashi, Y; Tamaki, K; Sato, S; Tedder, TF; Fujimoto, M
MLA Citation
Nakashima, H, Hamaguchi, Y, Watanabe, R, Ishiura, N, Kuwano, Y, Okochi, H, Takahashi, Y, Tamaki, K, Sato, S, Tedder, TF, and Fujimoto, M. "CD22 expression mediates the regulatory functions of peritoneal B-1a cells during the remission phase of contact hypersensitivity reactions." J Immunol 184.9 (May 1, 2010): 4637-4645.
PMID
20335532
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
184
Issue
9
Publish Date
2010
Start Page
4637
End Page
4645
DOI
10.4049/jimmunol.0901719

Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity.

B cells play critical roles in the pathogenesis of lupus. To examine the influence of B cells on disease pathogenesis in a murine lupus model, New Zealand Black and New Zealand White F(1) hybrid (NZB/W) mice were generated that were deficient for CD19 (CD19(-/-) NZB/W mice), a B cell-specific cell surface molecule that is essential for optimal B cell signal transduction. The emergence of anti-nuclear Abs was significantly delayed in CD19(-/-) NZB/W mice compared with wild type NZB/W mice. However, the pathologic manifestations of nephritis appeared significantly earlier, and survival was significantly reduced in CD19(-/-) NZB/W mice compared with wild type mice. These results demonstrate both disease-promoting and protective roles for B cells in lupus pathogenesis. Recent studies have identified a potent regulatory B cell subset (B10 cells) within the rare CD1d(hi)CD5(+) B cell subset of the spleen that regulates acute inflammation and autoimmunity through the production of IL-10. In wild type NZB/W mice, the CD1d(hi)CD5(+)B220(+) B cell subset that includes B10 cells was increased by 2.5-fold during the disease course, whereas CD19(-/-) NZB/W mice lacked this CD1d(hi)CD5(+) regulatory B cell subset. However, the transfer of splenic CD1d(hi)CD5(+) B cells from wild type NZB/W mice into CD19(-/-) NZB/W recipients significantly prolonged their survival. Furthermore, regulatory T cells were significantly decreased in CD19(-/-) NZB/W mice, but the transfer of wild type CD1d(hi)CD5(+) B cells induced T regulatory cell expansion in CD19(-/-) NZB/W mice. These results demonstrate an important protective role for regulatory B10 cells in this systemic autoimmune disease.

Authors
Watanabe, R; Ishiura, N; Nakashima, H; Kuwano, Y; Okochi, H; Tamaki, K; Sato, S; Tedder, TF; Fujimoto, M
MLA Citation
Watanabe, R, Ishiura, N, Nakashima, H, Kuwano, Y, Okochi, H, Tamaki, K, Sato, S, Tedder, TF, and Fujimoto, M. "Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity." J Immunol 184.9 (May 1, 2010): 4801-4809.
PMID
20368271
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
184
Issue
9
Publish Date
2010
Start Page
4801
End Page
4809
DOI
10.4049/jimmunol.0902385

Regulatory B cells that produce IL-10: a breath of fresh air in allergic airway disease.

Authors
Tedder, TF; Matsushita, T
MLA Citation
Tedder, TF, and Matsushita, T. "Regulatory B cells that produce IL-10: a breath of fresh air in allergic airway disease." J Allergy Clin Immunol 125.5 (May 2010): 1125-1127.
PMID
20451042
Source
pubmed
Published In
Journal of Allergy and Clinical Immunology
Volume
125
Issue
5
Publish Date
2010
Start Page
1125
End Page
1127
DOI
10.1016/j.jaci.2010.03.024

B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice.

B lymphocytes can both positively and negatively regulate cellular immune responses. Previous studies have demonstrated augmented T cell-mediated tumor immunity in genetically B cell-deficient mice, suggesting that therapeutic B cell depletion would enhance tumor immunity. To test this hypothesis and quantify B cell contributions to T cell-mediated anti-tumor immune responses, mature B cells were depleted from wild-type adult mice using CD20 mAb prior to syngeneic B16 melanoma tumor transfers. Remarkably, s.c. tumor volume and lung metastasis were increased 2-fold in B cell-depleted mice. Effector-memory and IFN-gamma-or TNF-alpha-secreting CD4(+) and CD8(+) T cell induction was significantly impaired in B cell-depleted mice with tumors. Tumor Ag-specific CD8(+) T cell proliferation was also impaired in tumor-bearing mice that lacked B cells. Thus, B cells were required for optimal T cell activation and cellular immunity in this in vivo nonlymphoid tumor model. Although B cells may not have direct effector roles in tumor immunity, impaired T cell activation, and enhanced tumor growth in the absence of B cells argue against previous proposals to augment tumor immunity through B cell depletion. Rather, targeting tumor Ags to B cells in addition to dendritic cells is likely to optimize tumor-directed vaccines and immunotherapies.

Authors
DiLillo, DJ; Yanaba, K; Tedder, TF
MLA Citation
DiLillo, DJ, Yanaba, K, and Tedder, TF. "B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice." J Immunol 184.7 (April 1, 2010): 4006-4016.
PMID
20194720
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
184
Issue
7
Publish Date
2010
Start Page
4006
End Page
4016
DOI
10.4049/jimmunol.0903009

Differential phosphorylation of functional tyrosines in CD19 modulates B-lymphocyte activation.

CD19 is a B-cell transmembrane molecule that is critical for B-cell activation. CD19 serves as a scaffold protein for key signal transduction molecules including Lyn, PI3K, and Vav, by providing docking sites for these molecules via phosphorylation of CD19-Y(513), CD19-Y(482), and CD19-Y(391). We investigated the process of CD19 tyrosine phophorylation during B-cell activation using Ab specific for each of these phosphorylated tyrosines. BCR engagement induced differential tyrosine phosphorylation, as CD19-Y(513) phophorylation occurred first, and CD19-Y(482) phosphorylation was delayed and transient. Different BCR isotypes exhibited distinct patterns of CD19 phosphorylation: IgG-BCR ligation resulted in faster phosphorylation of CD19-Y(513) and more intense phosphorylation of CD19-Y(391) than IgM-BCR ligation. This affected CD19-mediated downstream pathways involving Vav, PI3K, and Akt. Additionally, the phosphorylation profile of CD19 differed distinctly according to its plasma membrane location. CD19 phosphorylated at Y(513) was almost exclusively located within lipid rafts, whereas phosphorylated Y(482) and Y(391) were found both inside and outside of the rafts. Furthermore, the phosphorylation of all three tyrosines was remarkably enhanced and prolonged following the simultaneous stimulation of BCR and CD40. Thus, variations in phosphorylation patterns may contribute to the complexity of CD19-regulated signal transduction.

Authors
Ishiura, N; Nakashima, H; Watanabe, R; Kuwano, Y; Adachi, T; Takahashi, Y; Tsubata, T; Okochi, H; Tamaki, K; Tedder, TF; Fujimoto, M
MLA Citation
Ishiura, N, Nakashima, H, Watanabe, R, Kuwano, Y, Adachi, T, Takahashi, Y, Tsubata, T, Okochi, H, Tamaki, K, Tedder, TF, and Fujimoto, M. "Differential phosphorylation of functional tyrosines in CD19 modulates B-lymphocyte activation." Eur J Immunol 40.4 (April 2010): 1192-1204.
PMID
20101619
Source
pubmed
Published In
European Journal of Immunology
Volume
40
Issue
4
Publish Date
2010
Start Page
1192
End Page
1204
DOI
10.1002/eji.200939848

Innate and adaptive receptors interact to balance humoral immunity.

Authors
Tedder, TF
MLA Citation
Tedder, TF. "Innate and adaptive receptors interact to balance humoral immunity." J Immunol 184.5 (March 1, 2010): 2231-2232.
PMID
20164432
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
184
Issue
5
Publish Date
2010
Start Page
2231
End Page
2232
DOI
10.4049/jimmunol.1090001

CD20 deficiency in humans results in impaired T cell-independent antibody responses.

CD20 was the first B cell differentiation antigen identified, and CD20-specific mAbs are commonly used for the treatment of B cell malignancies and autoantibody-mediated autoimmune diseases. Despite this the role of CD20 in human B cell physiology has remained elusive. We describe here a juvenile patient with CD20 deficiency due to a homozygous mutation in a splice junction of the CD20 gene (also known as MS4A1) that results in "cryptic" splicing and nonfunctional mRNA species. Analysis of this patient has led us to conclude that CD20 has a central role in the generation of T cell-independent (TI) antibody responses. Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient. Consistent with this, TI antipolysaccharide B cell responses were severely impeded in CD20-deficient mice. Our study therefore identifies what we believe to be a novel type of humoral immunodeficiency caused by CD20 deficiency and characterized by normal development of antigen-independent B cells, along with a reduced capacity to mount proper antibody responses.

Authors
Kuijpers, TW; Bende, RJ; Baars, PA; Grummels, A; Derks, IAM; Dolman, KM; Beaumont, T; Tedder, TF; van Noesel, CJM; Eldering, E; van Lier, RAW
MLA Citation
Kuijpers, TW, Bende, RJ, Baars, PA, Grummels, A, Derks, IAM, Dolman, KM, Beaumont, T, Tedder, TF, van Noesel, CJM, Eldering, E, and van Lier, RAW. "CD20 deficiency in humans results in impaired T cell-independent antibody responses." J Clin Invest 120.1 (January 2010): 214-222.
Website
http://hdl.handle.net/10161/4326
PMID
20038800
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
120
Issue
1
Publish Date
2010
Start Page
214
End Page
222
DOI
10.1172/JCI40231

B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer.

The ability of B cells to negatively regulate cellular immune responses and inflammation has only recently been described. Hallmark papers from a number of distinguished laboratories have identified phenotypically diverse B-cell subsets with regulatory functions during distinct autoimmune diseases, including IL-10-producing B cells, CD5+ B-1a cells, CD1d+ marginal zone B cells, and transitional-2-marginal zone precursor B cells. Most recently, a numerically rare and phenotypically unique CD1dhiCD5+CD19hi subset of regulatory B cells has been identified in the spleens of both normal and autoimmune mice. CD1dhiCD5+ B cells with the capacity to produce IL-10 have been named B10 cells as they produce IL-10 exclusively and are the predominant B-cell source of IL-10. Remarkably, B10 cells are potent negative regulators of inflammation and autoimmunity in mouse models of disease in vivo. Herein, our current understanding of B10-cell development and function is reviewed in the context of previous studies that have identified and characterized regulatory B cells, emerging evidence for B10-cell regulation of tumor immunity, and the likelihood that B10 cells exist in humans.

Authors
DiLillo, DJ; Matsushita, T; Tedder, TF
MLA Citation
DiLillo, DJ, Matsushita, T, and Tedder, TF. "B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer." Ann N Y Acad Sci 1183 (January 2010): 38-57. (Review)
PMID
20146707
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1183
Publish Date
2010
Start Page
38
End Page
57
DOI
10.1111/j.1749-6632.2009.05137.x

CD19 REGULATES THE DEVELOPMENT OF BLEOMYCIN-INDUCED PULMONARY FIBROSIS

Authors
Komura, K; Yanaba, K; Horikawa, M; Ogawa, F; Fujimoto, M; Tedder, TF; Varga, J; Sato, S
MLA Citation
Komura, K, Yanaba, K, Horikawa, M, Ogawa, F, Fujimoto, M, Tedder, TF, Varga, J, and Sato, S. "CD19 REGULATES THE DEVELOPMENT OF BLEOMYCIN-INDUCED PULMONARY FIBROSIS." CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 28.2 (2010): S74-S74.
Source
wos-lite
Published In
Clinical and experimental rheumatology
Volume
28
Issue
2
Publish Date
2010
Start Page
S74
End Page
S74

Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice.

We have established a model of leukemia immunotherapy using T cells expressing chimeric T-cell receptors (cTCRs) targeting the CD20 molecule expressed on normal and neoplastic B cells. After transfer into human CD20 (hCD20) transgenic mice, cTCR(+) T cells showed antigen-specific delayed egress from the lungs, concomitant with T-cell deletion. Few cTCR(+) T cells reached the bone marrow (BM) in hCD20 transgenic mice, precluding effectiveness against leukemia. Anti-hCD20 antibody-mediated B-cell depletion before adoptive T-cell therapy permitted egress of mouse CD20-specific cTCR(+) T cells from the lungs, enhanced T-cell survival, and promoted cTCR(+) T cell-dependent elimination of established mouse CD20(+) leukemia. Furthermore, CD20-specific cTCR(+) T cells eliminated residual B cells refractory to depletion with monoclonal antibodies. These findings suggest that combination of antibody therapy that depletes antigen-expressing normal tissues with adoptive T-cell immunotherapy enhances the ability of cTCR(+) T cells to survive and control tumors.

Authors
James, SE; Orgun, NN; Tedder, TF; Shlomchik, MJ; Jensen, MC; Lin, Y; Greenberg, PD; Press, OW
MLA Citation
James, SE, Orgun, NN, Tedder, TF, Shlomchik, MJ, Jensen, MC, Lin, Y, Greenberg, PD, and Press, OW. "Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice." Blood 114.27 (December 24, 2009): 5454-5463.
PMID
19880489
Source
pubmed
Published In
Blood
Volume
114
Issue
27
Publish Date
2009
Start Page
5454
End Page
5463
DOI
10.1182/blood-2009-08-232967

CD19: a promising B cell target for rheumatoid arthritis.

B-cell depletion with unconjugated CD20 monoclonal antibody (mAb) is used to treat rheumatoid arthritis and other autoimmune diseases. CD20-targeted immunotherapy depletes mature B cells through monocyte-mediated antibody-dependent cellular cytotoxicity, but does not effectively deplete pre-B or immature B cells, certain peripheral B cell subpopulations, most antibody-producing cells, or their malignant counterparts. As immature B cells expressing autoreactive antigen receptors are not depleted by anti-CD20 mAb, a new strategy for eliminating autoantigen-selected B cells and for treating early lymphoblastic leukemias and/or lymphomas was developed using CD19-specific mAbs that induce Fcgamma receptor-dependent and monocyte-dependent B-cell depletion. Preclinical studies using transgenic mice expressing human CD19 have shown that pre-B cells and their malignant counterparts, as well as pre-existing antibody-producing and autoantibody-producing cells, are depleted. Therefore, CD19-directed immunotherapy is expected to treat diverse pre-B-cell-related and plasmablast-related malignancies, and humoral transplant rejection. Moreover, in contrast to CD20-directed immunotherapies, CD19 mAbs could purge the B cell repertoire of autoreactive clones and reset the developmental clock to a point that curtails the extent of emerging self-reactivity, in addition to reducing autoreactive T-cell activation through the elimination of mature B cells. Humanized CD19 mAbs are expected to enter clinical trials in 2009, offering a new approach for the treatment of autoimmune disease that removes both immature B cells and antibodies with autoreactive specificities. CD19-directed immunotherapy could, therefore, offer a new horizon in B-cell depletion for the treatment of multiple autoimmune diseases.

Authors
Tedder, TF
MLA Citation
Tedder, TF. "CD19: a promising B cell target for rheumatoid arthritis." Nat Rev Rheumatol 5.10 (October 2009): 572-577. (Review)
PMID
19798033
Source
pubmed
Published In
Nature Reviews Rheumatology
Volume
5
Issue
10
Publish Date
2009
Start Page
572
End Page
577
DOI
10.1038/nrrheum.2009.184

CD21/35 promotes protective immunity to Streptococcus pneumoniae through a complement-independent but CD19-dependent pathway that regulates PD-1 expression.

Humoral immunity to T cell-independent type 2 Ags (TI-2 Ag) is critical for protection against encapsulated bacteria such as Streptococcus pneumoniae. The CD21/35 receptor is thought to promote protective humoral immunity to encapsulated bacteria by enabling complement-decorated capsular polysaccharides to coligate the CD21/35-CD19 signaling complex with the B cell Ag receptor (BCR), thereby enhancing Ag-specific B cell activation. However, Ab responses to S. pneumoniae type 3 capsular polysaccharide (PPS-3) and other strong TI-2 Ags were significantly impaired in CD21/35(-/-) but not C3(-/-) or C4(-/-) mice. B cells from CD21/35(-/-) mice expressed significantly higher levels of cell surface CD19. CD21/35(-/-) B cells exhibited enhanced BCR-induced calcium responses and significantly higher expression of the inhibitory programmed death-1 (PD-1) receptor following immunization with a TI-2 Ag or BCR crosslinking. Reducing CD19 expression in CD21/35(-/-) mice normalized BCR-induced calcium responses, PD-1 induction, and PPS-3-specific IgG3 responses and restored protection during S. pneumoniae infection. PD-1 blockade also selectively rescued PPS-3-specific IgG3 responses in CD21/35(-/-) mice. Thereby, CD21/35 promotes protective humoral immunity to S. pneumoniae and other strong TI-2 Ags through a complement-independent pathway by negatively regulating CD19 expression and PD-1 induction.

Authors
Haas, KM; Poe, JC; Tedder, TF
MLA Citation
Haas, KM, Poe, JC, and Tedder, TF. "CD21/35 promotes protective immunity to Streptococcus pneumoniae through a complement-independent but CD19-dependent pathway that regulates PD-1 expression." J Immunol 183.6 (September 15, 2009): 3661-3671.
PMID
19710450
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
183
Issue
6
Publish Date
2009
Start Page
3661
End Page
3671
DOI
10.4049/jimmunol.0901218

CD19, a response regulator of B lymphocytes, regulates wound healing through hyaluronan-induced TLR4 signaling.

Immune cells are critical to the wound-healing process, through both cytokine and growth factor secretion. Although previous studies have revealed that B cells are present within wound tissue, little is known about the role of B cells in wound healing. To clarify this, we investigated cutaneous wound healing in mice either lacking or overexpressing CD19, a critical positive-response regulator of B cells. CD19 deficiency inhibited wound healing, infiltration of neutrophils and macrophages, and cytokine expression, including basic and acidic fibroblast growth factor, interleukin-6, platelet-derived growth factor, and transforming growth factor-beta. By contrast, CD19 overexpression enhanced wound healing and cytokine expression. Hyaluronan (HA), an endogenous ligand for toll-like receptor (TLR)-4, stimulated B cells, which infiltrates into wounds to produce interleukin-6 and transforming growth factor-beta through TLR4 in a CD19-dependent manner. CD19 expression regulated TLR4 signaling through p38 activation. HA accumulation was increased in injured skin tissue relative to normal skin, and exogenous application of HA promoted wound repair in wild-type but not CD19-deficient mice, suggesting that the beneficial effects of HA to the wound-healing process are CD19-dependent. Collectively, these results suggest that increased HA accumulation in injured skin induces cytokine production by stimulating B cells through TLR4 in a CD19-dependent manner. Thus, this study is the first to reveal a critical role of B cells and novel mechanisms in wound healing.

Authors
Iwata, Y; Yoshizaki, A; Komura, K; Shimizu, K; Ogawa, F; Hara, T; Muroi, E; Bae, S; Takenaka, M; Yukami, T; Hasegawa, M; Fujimoto, M; Tomita, Y; Tedder, TF; Sato, S
MLA Citation
Iwata, Y, Yoshizaki, A, Komura, K, Shimizu, K, Ogawa, F, Hara, T, Muroi, E, Bae, S, Takenaka, M, Yukami, T, Hasegawa, M, Fujimoto, M, Tomita, Y, Tedder, TF, and Sato, S. "CD19, a response regulator of B lymphocytes, regulates wound healing through hyaluronan-induced TLR4 signaling." Am J Pathol 175.2 (August 2009): 649-660.
PMID
19574428
Source
pubmed
Published In
The American journal of pathology
Volume
175
Issue
2
Publish Date
2009
Start Page
649
End Page
660
DOI
10.2353/ajpath.2009.080355

Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism.

Commensal bacteria in the lower intestine of mammals are 10 times as numerous as the body's cells. We investigated the relative importance of different immune mechanisms in limiting the spread of the intestinal microbiota. Here, we reveal a flexible continuum between innate and adaptive immune function in containing commensal microbes. Mice deficient in critical innate immune functions such as Toll-like receptor signaling or oxidative burst production spontaneously produce high-titer serum antibodies against their commensal microbiota. These antibody responses are functionally essential to maintain host-commensal mutualism in vivo in the face of innate immune deficiency. Spontaneous hyper-activation of adaptive immunity against the intestinal microbiota, secondary to innate immune deficiency, may clarify the underlying mechanisms of inflammatory diseases where immune dysfunction is implicated.

Authors
Slack, E; Hapfelmeier, S; Stecher, B; Velykoredko, Y; Stoel, M; Lawson, MAE; Geuking, MB; Beutler, B; Tedder, TF; Hardt, W-D; Bercik, P; Verdu, EF; McCoy, KD; Macpherson, AJ
MLA Citation
Slack, E, Hapfelmeier, S, Stecher, B, Velykoredko, Y, Stoel, M, Lawson, MAE, Geuking, MB, Beutler, B, Tedder, TF, Hardt, W-D, Bercik, P, Verdu, EF, McCoy, KD, and Macpherson, AJ. "Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism." Science 325.5940 (July 31, 2009): 617-620.
PMID
19644121
Source
pubmed
Published In
Science
Volume
325
Issue
5940
Publish Date
2009
Start Page
617
End Page
620
DOI
10.1126/science.1172747

Targeting B-cells mitigates autoimmune diabetes in NOD mice: what is plan B?

Authors
Smith, SH; Tedder, TF
MLA Citation
Smith, SH, and Tedder, TF. "Targeting B-cells mitigates autoimmune diabetes in NOD mice: what is plan B?." Diabetes 58.7 (July 2009): 1479-1481.
PMID
19564459
Source
pubmed
Published In
Diabetes
Volume
58
Issue
7
Publish Date
2009
Start Page
1479
End Page
1481
DOI
10.2337/db09-0497

The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.

Autoimmunity and inflammation are controlled in part by regulatory B cells, including a recently identified IL-10-competent CD1d(high)CD5(+) B cell subset termed B10 cells that represents 1-3% of adult mouse spleen B cells. In this study, pathways that influence B10 cell generation and IL-10 production were identified and compared with previously described regulatory B cells. IL-10-competent B cells were predominantly CD1d(high)CD5(+) in adult spleen and were the prevalent source of IL-10, but not other cytokines. B10 cell development and/or maturation in vivo required Ag receptor diversity and intact signaling pathways, but not T cells, gut-associated flora, or environmental pathogens. Spleen B10 cell frequencies were significantly expanded in aged mice and mice predisposed to autoimmunity, but were significantly decreased in mouse strains that are susceptible to exogenous autoantigen-induced autoimmunity. LPS, PMA, plus ionomycin stimulation in vitro for 5 h induced B10 cells to express cytoplasmic IL-10. However, prolonged LPS or CD40 stimulation (48 h) induced additional adult spleen CD1d(high)CD5(+) B cells to express IL-10 following PMA plus ionomycin stimulation. Prolonged LPS or CD40 stimulation of newborn spleen and adult blood or lymph node CD1d(low) and/or CD5(-) B cells also induced cytoplasmic IL-10 competence in rare B cells, with CD40 ligation uniformly inducing CD5 expression. IL-10 secretion was induced by LPS signaling through MyD88-dependent pathways, but not following CD40 ligation. LPS stimulation also induced rapid B10 cell clonal expansion when compared with other spleen B cells. Thereby, both adaptive and innate signals regulate B10 cell development, maturation, CD5 expression, and competence for IL-10 production.

Authors
Yanaba, K; Bouaziz, J-D; Matsushita, T; Tsubata, T; Tedder, TF
MLA Citation
Yanaba, K, Bouaziz, J-D, Matsushita, T, Tsubata, T, and Tedder, TF. "The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals." J Immunol 182.12 (June 15, 2009): 7459-7472.
PMID
19494269
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
182
Issue
12
Publish Date
2009
Start Page
7459
End Page
7472
DOI
10.4049/jimmunol.0900270

Establishment of experimental eosinophilic vasculitis by IgE-mediated cutaneous reverse passive arthus reaction.

Prominent eosinophil infiltration is a characteristic of some forms of vasculitis, such as Churg-Strauss syndrome, also known as allergic granulomatous vasculitis. In the current study, we established a mouse model of cutaneous eosinophilic vasculitis by the cutaneous reverse passive Arthus reaction using IgE injection instead of IgG. Wild-type C57BL/6 mice were injected with IgE anti-trinitrophenyl antibodies, followed immediately by intravenous administration of trinitrophenyl bovine serum albumin. IgE-mediated immune complex challenge induced substantial hemorrhage with marked infiltration of eosinophils in which neutrophils, mast cells, and macrophages were also mixed. This finding contrasted remarkably with the neutrophil-dominant infiltration pattern in IgG-mediated immune complex challenge. In the lesion, the expression level of monocyte chemotactic protein-3 was increased, and anti-monocyte chemotactic protein-3 treatment resulted in a significant but incomplete blockade of eosinophil recruitment. Furthermore, mice lacking E-selectin, P-selectin, L-selectin, or intercellular adhesion molecule-1, as well as wild-type mice that received anti-vascular cell adhesion molecule-1-blocking antibodies were assessed for the IgE-mediated Arthus reaction. After 24 hours, the loss of P-selectin resulted in a significant reduction in eosinophil accumulation compared with both wild-type mice and other mouse mutants. Collectively, the Fc class of immunoglobulins, which forms these immune complexes, critically determines the disease manifestation of vasculitis. The IgE-mediated cutaneous reverse passive Arthus reaction may serve as an experimental model for cutaneous eosinophilic infiltration in vasculitis as well as in other diseases.

Authors
Ishii, T; Fujita, T; Matsushita, T; Yanaba, K; Hasegawa, M; Nakashima, H; Ogawa, F; Shimizu, K; Takehara, K; Tedder, TF; Sato, S; Fujimoto, M
MLA Citation
Ishii, T, Fujita, T, Matsushita, T, Yanaba, K, Hasegawa, M, Nakashima, H, Ogawa, F, Shimizu, K, Takehara, K, Tedder, TF, Sato, S, and Fujimoto, M. "Establishment of experimental eosinophilic vasculitis by IgE-mediated cutaneous reverse passive arthus reaction." Am J Pathol 174.6 (June 2009): 2225-2233.
PMID
19389931
Source
pubmed
Published In
The American journal of pathology
Volume
174
Issue
6
Publish Date
2009
Start Page
2225
End Page
2233
DOI
10.2353/ajpath.2009.080223

B cells contribute to ischemia/reperfusion-mediated tissue injury.

Multiple elements are known to participate in ischemia/reperfusion (I/R)-mediated tissue injury. Amongst them, B cells have been shown to contribute by the production of antibodies that bind to ischemic cells and fix complement. It is currently unknown whether B cells participate through antibody-independent mechanisms in the pathogenesis of I/R. In a mesenteric I/R model we found that B cells infiltrate the injured intestine of normal and autoimmune mice 2h after reperfusion is established. B cell depletion protected mice from the development of I/R-mediated intestinal damage. The protection conferred by B cell depletion was significantly greater in MRL/lpr mice. Finally, we show that ischemic tissue expressed the B cell-attractant CXCL13 and infiltrating B cells expressed the corresponding receptor CXCR5. Our data grant B cells an antibody-independent role in the pathogenesis of intestinal I/R and suggest that B cells accumulate in the injured tissue in response to the chemokine CXCL13.

Authors
Chen, J; Crispín, JC; Tedder, TF; Dalle Lucca, J; Tsokos, GC
MLA Citation
Chen, J, Crispín, JC, Tedder, TF, Dalle Lucca, J, and Tsokos, GC. "B cells contribute to ischemia/reperfusion-mediated tissue injury." J Autoimmun 32.3-4 (May 2009): 195-200.
PMID
19342197
Source
pubmed
Published In
Journal of Autoimmunity
Volume
32
Issue
3-4
Publish Date
2009
Start Page
195
End Page
200
DOI
10.1016/j.jaut.2009.02.021

B-lymphocyte depletion for the treatment of multiple sclerosis: now things really get interesting.

Authors
Matsushita, T; Tedder, TF
MLA Citation
Matsushita, T, and Tedder, TF. "B-lymphocyte depletion for the treatment of multiple sclerosis: now things really get interesting." Expert Rev Neurother 9.3 (March 2009): 309-312.
PMID
19271937
Source
pubmed
Published In
Expert Review of Neurotherapeutics
Volume
9
Issue
3
Publish Date
2009
Start Page
309
End Page
312
DOI
10.1586/14737175.9.3.309

Intercellular adhesion molecule-1 expression on fibroblasts contributes to the development of skin fibrosis in tight-skin mice

Authors
Hasegawa, M; Matsushita, Y; Matsushita, T; Fujimoto, M; Steeber, DA; Tedder, TF; Takehara, K; Sato, S
MLA Citation
Hasegawa, M, Matsushita, Y, Matsushita, T, Fujimoto, M, Steeber, DA, Tedder, TF, Takehara, K, and Sato, S. "Intercellular adhesion molecule-1 expression on fibroblasts contributes to the development of skin fibrosis in tight-skin mice." CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 27.3 (2009): S73-S73.
Source
wos-lite
Published In
Clinical and experimental rheumatology
Volume
27
Issue
3
Publish Date
2009
Start Page
S73
End Page
S73

An L-selectin ligand distinct from P-selectin glycoprotein ligand-1 is expressed on endothelial cells and promotes neutrophil rolling in inflammation.

Neutrophils recruited from the blood are key players in the innate immune response. Selectins play critical roles in neutrophil recruitment by mediating their tethering and rolling in inflamed venules. While the roles of P- and E-selectin in this process are well established, the mechanisms of L-selectin-mediated neutrophil recruitment remain elusive. One proposal is that tethering is mediated by L-selectin on flowing neutrophils interacting with P-selectin glycoprotein ligand-1 (PSGL-1) on adherent neutrophils. To clarify whether L-selectin-mediated neutrophil recruitment depends entirely on PSGL-1, we examined the impact of L-selectin deficiency in mice with a PSGL-1-deficient background. L-selectin and PSGL-1 double-knockout mice exhibited a higher increase in their peripheral blood neutrophil count and a worse defect in neutrophil recruitment into the inflamed peritoneum than PSGL-1-deficient mice. Intravital microscopy of inflamed cremaster muscle venules showed that L-selectindeficiency or antibody blockade of L-selectin reduced the residual leukocyte rolling in PSGL-1-deficient mice. Flow cytometric analyses showed that the endothelial cells from the cremaster muscle bound L-selectin in a PSGL-1-independent manner. These results provide evidence for the existence of an L-selectin ligand distinct from PSGL-1 in inflammation and indicate that such a ligand is expressed on endothelial cells, promoting neutrophil rolling in vivo.

Authors
Shigeta, A; Matsumoto, M; Tedder, TF; Lowe, JB; Miyasaka, M; Hirata, T
MLA Citation
Shigeta, A, Matsumoto, M, Tedder, TF, Lowe, JB, Miyasaka, M, and Hirata, T. "An L-selectin ligand distinct from P-selectin glycoprotein ligand-1 is expressed on endothelial cells and promotes neutrophil rolling in inflammation." Blood 112.13 (December 15, 2008): 4915-4923.
PMID
18818390
Source
pubmed
Published In
Blood
Volume
112
Issue
13
Publish Date
2008
Start Page
4915
End Page
4923
DOI
10.1182/blood-2008-04-153866

CD19 regulates the development of bleomycin-induced pulmonary fibrosis in a mouse model.

OBJECTIVE: The contribution of CD19 and B lymphocytes to pulmonary fibrosis is controversial. The aim of this study was to address the role of CD19 during the development of pulmonary fibrosis. METHODS: Mice lacking or overexpressing the B cell surface molecule CD19, which is known as a positive regulator of B cell activation, were used in a model of bleomycin-induced pulmonary fibrosis. Ten or sixteen days after intratracheal injection of bleomycin, lung sections from mice were evaluated by histologic analysis. Seven days after instillation, the total leukocyte count and the number of B cells in bronchoalveolar lavage fluid (BALF) were determined, using a hemocytometer and flow cytometry. Bleomycin was also administered into selectin-deficient or intercellular adhesion molecule 1-deficient mouse strains. The level of CXCR3 expression on B cells was determined by flow cytometry. RESULTS: CD19 deficiency significantly reduced susceptibility to intratracheal bleomycin challenge on day 16, while CD19 overexpression augmented fibrosis even on day 10. Furthermore, the survival rate and number of B cells in BALF also correlated with CD19 expression levels. The accumulation of B cells in BALF was dependent on CD19 levels, whereas there was no association with the levels of selectins or intercellular adhesion molecule 1. Additionally, CXCR3 was up-regulated in BALF B cells, while it was rarely expressed on circulating B cells. Furthermore, CD19 signaling facilitated B cell CXCR3 up-regulation in response to stimulation in vitro. CONCLUSION: These results suggest that CD19 signaling is associated with the development of pulmonary fibrosis by controlling B cell infiltration into lung tissue, which may be associated with CXCR3 up-regulation.

Authors
Komura, K; Yanaba, K; Horikawa, M; Ogawa, F; Fujimoto, M; Tedder, TF; Sato, S
MLA Citation
Komura, K, Yanaba, K, Horikawa, M, Ogawa, F, Fujimoto, M, Tedder, TF, and Sato, S. "CD19 regulates the development of bleomycin-induced pulmonary fibrosis in a mouse model." Arthritis Rheum 58.11 (November 2008): 3574-3584.
PMID
18975313
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
58
Issue
11
Publish Date
2008
Start Page
3574
End Page
3584
DOI
10.1002/art.23995

Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression.

EAE is a mouse T cell-mediated autoimmune disease of the CNS used to model the human condition MS. The contributions of B cells to EAE initiation and progression are unclear. In this study, we have shown that EAE disease initiation and progression are differentially influenced by the depletion of B cells from mice with otherwise intact immune systems. CD20 antibody-mediated B cell depletion before EAE induction substantially exacerbated disease symptoms and increased encephalitogenic T cell influx into the CNS. Increased symptom severity resulted from the depletion of a rare IL-10-producing CD1dhiCD5+ regulatory B cell subset (B10 cells), since the adoptive transfer of splenic B10 cells before EAE induction normalized EAE in B cell-depleted mice. While transfer of regulatory B10 cells was maximally effective during early EAE initiation, they had no obvious role during disease progression. Rather, B cell depletion during EAE disease progression dramatically suppressed symptoms. Specifically, B cells were required for the generation of CD4+ T cells specific for CNS autoantigen and the entry of encephalitogenic T cells into the CNS during disease progression. These results demonstrate reciprocal regulatory roles for B cells during EAE immunopathogenesis. The therapeutic effect of B cell depletion for the treatment of autoimmunity may therefore depend on the relative contributions and the timing of these opposing B cell activities during the course of disease initiation and pathogenesis.

Authors
Matsushita, T; Yanaba, K; Bouaziz, J-D; Fujimoto, M; Tedder, TF
MLA Citation
Matsushita, T, Yanaba, K, Bouaziz, J-D, Fujimoto, M, and Tedder, TF. "Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression." J Clin Invest 118.10 (October 2008): 3420-3430.
PMID
18802481
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
118
Issue
10
Publish Date
2008
Start Page
3420
End Page
3430
DOI
10.1172/JCI36030

B lymphocytes: how they develop and function.

The discovery that lymphocyte subpopulations participate in distinct components of the immune response focused attention onto the origins and function of lymphocytes more than 40 years ago. Studies in the 1960s and 1970s demonstrated that B and T lymphocytes were responsible primarily for the basic functions of antibody production and cell-mediated immune responses, respectively. The decades that followed have witnessed a continuum of unfolding complexities in B-cell development, subsets, and function that could not have been predicted. Some of the landmark discoveries that led to our current understanding of B lymphocytes as the source of protective innate and adaptive antibodies are highlighted in this essay. The phenotypic and functional diversity of B lymphocytes, their regulatory roles independent of antibody production, and the molecular events that make this lineage unique are also considered. Finally, perturbations in B-cell development that give rise to certain types of congenital immunodeficiency, leukemia/lymphoma, and autoimmune disease are discussed in the context of normal B-cell development and selection. Despite the significant advances that have been made at the cellular and molecular levels, there is much more to learn, and cross-disciplinary studies in hematology and immunology will continue to pave the way for new discoveries.

Authors
LeBien, TW; Tedder, TF
MLA Citation
LeBien, TW, and Tedder, TF. "B lymphocytes: how they develop and function." Blood 112.5 (September 1, 2008): 1570-1580. (Review)
PMID
18725575
Source
pubmed
Published In
Blood
Volume
112
Issue
5
Publish Date
2008
Start Page
1570
End Page
1580
DOI
10.1182/blood-2008-02-078071

Lymphoma depletion during CD20 immunotherapy in mice is mediated by macrophage FcgammaRI, FcgammaRIII, and FcgammaRIV.

Despite the demonstrated clinical efficacy of CD20 monoclonal antibody (mAb) for lymphoma therapy, the in vivo mechanisms of tumor depletion remain controversial and variable. To identify the molecular mechanisms responsible for lymphoma killing by CD20 mAb in a homologous system amenable to mechanistic studies and genetic manipulation, a mouse lymphoma model was developed using primary tumor cells from a C57BL/6 Emicro-cMyc transgenic mouse and mouse antimouse CD20 mAbs. CD20 mAb treatment of syngeneic mice with adoptively transferred lymphomas prevented tumor development or significantly prolonged mouse survival depending on tumor volume, mAb dose, and treatment timing. Cooperative FcgammaRIV, FcgammaRIII, and FcgammaRI interactions mediated optimal lymphoma depletion by CD20 mAb in vivo, whereas clodronate-mediated depletion of macrophages eliminated the therapeutic benefit of CD20 mAb. Although CD20 mAbs activated complement in vitro and in vivo, normal and malignant B-cell depletion was induced through C1q- and C3-independent mechanisms. Thus, the ability of CD20 mAbs to deplete malignant B cells in vivo required FcgammaR-dependent use of the innate mononuclear cell immune system. These findings allow for mechanism-based predictions of the biologic outcome of CD20 mAb therapy and treatment optimization.

Authors
Minard-Colin, V; Xiu, Y; Poe, JC; Horikawa, M; Magro, CM; Hamaguchi, Y; Haas, KM; Tedder, TF
MLA Citation
Minard-Colin, V, Xiu, Y, Poe, JC, Horikawa, M, Magro, CM, Hamaguchi, Y, Haas, KM, and Tedder, TF. "Lymphoma depletion during CD20 immunotherapy in mice is mediated by macrophage FcgammaRI, FcgammaRIII, and FcgammaRIV." Blood 112.4 (August 15, 2008): 1205-1213.
PMID
18495955
Source
pubmed
Published In
Blood
Volume
112
Issue
4
Publish Date
2008
Start Page
1205
End Page
1213
DOI
10.1182/blood-2008-01-135160

Regulatory B cells as inhibitors of immune responses and inflammation.

B cells positively regulate immune responses through antibody production and optimal CD4(+) T-cell activation. However, a specific and functionally important subset of B cells can also negatively regulate immune responses in mouse autoimmunity and inflammation models. The lack or loss of regulatory B cells has been demonstrated by exacerbated symptoms in experimental autoimmune encephalitis, chronic colitis, contact hypersensitivity, collagen-induced arthritis, and non-obese diabetic mouse models. Accumulating evidence suggests that B cells exert their regulatory role through the production of interleukin-10 (IL-10) by either B-1, marginal zone (MZ), or transitional 2-MZ precursor B-cell subsets. We have recently found that IL-10-producing regulatory B cells predominantly localize within a rare CD1d(hi)CD5(+) B-cell subset that shares cell surface markers with both B-1 and MZ B cells. We have labeled this specific subset of regulatory B cells as B10 cells to highlight that these rare CD1d(hi)CD5(+) B cells only produce IL-10 and are responsible for most IL-10 production by B cells and to distinguish them from other regulatory B-cell subsets that may also exist. This review focuses on the recent progress in this field and the exciting opportunities for understanding how this unique B-cell subset influences diverse immune functions.

Authors
Bouaziz, J-D; Yanaba, K; Tedder, TF
MLA Citation
Bouaziz, J-D, Yanaba, K, and Tedder, TF. "Regulatory B cells as inhibitors of immune responses and inflammation." Immunol Rev 224 (August 2008): 201-214. (Review)
PMID
18759928
Source
pubmed
Published In
Immunological Reviews
Volume
224
Publish Date
2008
Start Page
201
End Page
214
DOI
10.1111/j.1600-065X.2008.00661.x

B-lymphocyte contributions to human autoimmune disease.

SUMMARY: Autoimmunity results from abnormal B- and T-cell recognition of self-antigens, which leads to autoantibody production in many cases. Autoantibodies produced by B-cell-derived plasma cells provide diagnostic markers for autoimmunity but also contribute significantly to disease pathogenesis. As discussed in this review, the therapeutic benefit of depleting B cells in mice and humans has refocused attention on B cells and their role in autoimmunity beyond autoantibody production. B cells specifically serve as cellular adjuvants for CD4(+) T-cell activation, while regulatory B cells, including those that produce interleukin-10 (B10 cells), function as negative regulators of inflammatory immune responses. The emerging picture is that B cells, autoantibodies, and T cells are all important components of abnormal immune responses that lead to tissue pathology unique to each autoimmune disease, with their relative contributions changing during disease progression. Autoimmune diseases where B-cell functions are closely correlated with disease activity include systemic lupus erythematosus, rheumatoid arthritis, scleroderma, type 1 diabetes, and multiple sclerosis. Understanding the overlapping roles of B cells as mediators of autoimmune disease will facilitate the development of more precisely directed therapies and combination therapies with broader clinical efficacy than current depletion strategies that remove all B cells.

Authors
Yanaba, K; Bouaziz, J-D; Matsushita, T; Magro, CM; St Clair, EW; Tedder, TF
MLA Citation
Yanaba, K, Bouaziz, J-D, Matsushita, T, Magro, CM, St Clair, EW, and Tedder, TF. "B-lymphocyte contributions to human autoimmune disease." Immunol Rev 223 (June 2008): 284-299. (Review)
PMID
18613843
Source
pubmed
Published In
Immunological Reviews
Volume
223
Publish Date
2008
Start Page
284
End Page
299
DOI
10.1111/j.1600-065X.2008.00646.x

CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma.

Mice subcutaneously injected with bleomycin, in an experimental model of human systemic sclerosis, develop cutaneous and lung fibrosis with autoantibody production. CD19 is a general "rheostat" that defines signaling thresholds critical for humoral immune responses, autoimmunity, and cytokine production. To determine the role of CD19 in the bleomycin-induced systemic sclerosis model, we investigated the development of fibrosis and autoimmunity in CD19-deficient mice. Bleomycin-treated wild-type mice exhibited dermal and lung fibrosis, hyper-gamma-globulinemia, autoantibody production, and enhanced serum and skin expression of various cytokines, including fibrogenic interleukin-4, interleukin-6, and transforming growth factor-beta1, all of which were inhibited by CD19 deficiency. Bleomycin treatment enhanced hyaluronan production in the skin, lung, and sera. Addition of hyaluronan, an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4, stimulated B cells to produce various cytokines, primarily through TLR4; CD19 deficiency suppressed this stimulation. These results suggest that bleomycin induces fibrosis by enhancing hyaluronan production, which activates B cells to produce fibrogenic cytokines mainly via TLR4 and induce autoantibody production, and that CD19 deficiency suppresses fibrosis and autoantibody production by inhibiting TLR4 signals.

Authors
Yoshizaki, A; Iwata, Y; Komura, K; Ogawa, F; Hara, T; Muroi, E; Takenaka, M; Shimizu, K; Hasegawa, M; Fujimoto, M; Tedder, TF; Sato, S
MLA Citation
Yoshizaki, A, Iwata, Y, Komura, K, Ogawa, F, Hara, T, Muroi, E, Takenaka, M, Shimizu, K, Hasegawa, M, Fujimoto, M, Tedder, TF, and Sato, S. "CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma." Am J Pathol 172.6 (June 2008): 1650-1663.
PMID
18467694
Source
pubmed
Published In
The American journal of pathology
Volume
172
Issue
6
Publish Date
2008
Start Page
1650
End Page
1663
DOI
10.2353/ajpath.2008.071049

A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.

B cells mediate multiple functions that influence immune and inflammatory responses. In this study, T cell-mediated inflammation was exaggerated in CD19-deficient (Cd19(-/-)) mice and wild-type mice depleted of CD20(+) B cells, whereas inflammation was substantially reduced in mice with hyperactive B cells as a result of CD19 overexpression (hCD19Tg). These inflammatory responses were negatively regulated by a unique CD1d(hi)CD5(+) B cell subset that was absent in Cd19(-/-) mice, represented only 1%-2% of spleen B220(+) cells in wild-type mice, but was expanded to approximately 10% of spleen B220(+) cells in hCD19Tg mice. Adoptive transfer of these CD1d(hi)CD5(+) B cells normalized inflammation in wild-type mice depleted of CD20(+) B cells and in Cd19(-/-) mice. Remarkably, IL-10 production was restricted to this CD1d(hi)CD5(+) B cell subset, with IL-10 production diminished in Cd19(-/-) mice, yet increased in hCD19Tg mice. Thereby, CD1d(hi)CD5(+) B cells represent a unique subset of potent regulatory B cells.

Authors
Yanaba, K; Bouaziz, J-D; Haas, KM; Poe, JC; Fujimoto, M; Tedder, TF
MLA Citation
Yanaba, K, Bouaziz, J-D, Haas, KM, Poe, JC, Fujimoto, M, and Tedder, TF. "A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses." Immunity 28.5 (May 2008): 639-650.
PMID
18482568
Source
pubmed
Published In
Immunity
Volume
28
Issue
5
Publish Date
2008
Start Page
639
End Page
650
DOI
10.1016/j.immuni.2008.03.017

Distinctive tyrosine phosphorylation pattern of CD19 during BCR and CD40 signaling

Authors
Fujimoto, M; Ishiura, N; Adachi, T; Tsubata, T; Tedder, TF; Tamaki, K
MLA Citation
Fujimoto, M, Ishiura, N, Adachi, T, Tsubata, T, Tedder, TF, and Tamaki, K. "Distinctive tyrosine phosphorylation pattern of CD19 during BCR and CD40 signaling." FASEB JOURNAL 22 (April 2008).
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
22
Publish Date
2008

B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in Fc gamma R effector functions.

NOD mice deficient for B lymphocytes from birth fail to develop autoimmune or type 1 diabetes. To assess whether B cell depletion influences type 1 diabetes in mice with an intact immune system, NOD female mice representing early and late preclinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term CD20 mAb treatment in 5-wk-old NOD female mice reduced B cell numbers by approximately 95%, decreased subsequent insulitis, and prevented diabetes in >60% of littermates. In addition, CD20 mAb treatment of 15-wk-old NOD female mice significantly delayed, but did not prevent, diabetes onset. Protection from diabetes did not result from altered T cell numbers or subset distributions, or regulatory/suppressor T cell generation. Rather, impaired CD4+ and CD8+ T cell activation in the lymph nodes of B cell-depleted NOD mice may delay diabetes onset. B cell depletion was achieved despite reduced sensitivity of NOD mice to CD20 mAbs compared with C57BL/6 mice. Decreased B cell depletion resulted from deficient FcgammaRI binding of IgG2a/c CD20 mAbs and 60% reduced spleen monocyte numbers, which in combination reduced Ab-dependent cellular cytotoxicity. With high-dose CD20 mAb treatment (250 microg) in NOD mice, FcgammaRIII and FcgammaRIV compensated for inadequate FcgammaRI function and mediated B cell depletion. Thereby, NOD mice provide a model for human FcgammaR polymorphisms that reduce therapeutic mAb efficacy in vivo. Moreover, this study defines a new, clinically relevant approach whereby B cell depletion early in the course of disease development may prevent diabetes or delay progression of disease.

Authors
Xiu, Y; Wong, CP; Bouaziz, J-D; Hamaguchi, Y; Wang, Y; Pop, SM; Tisch, RM; Tedder, TF
MLA Citation
Xiu, Y, Wong, CP, Bouaziz, J-D, Hamaguchi, Y, Wang, Y, Pop, SM, Tisch, RM, and Tedder, TF. "B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in Fc gamma R effector functions." J Immunol 180.5 (March 1, 2008): 2863-2875.
PMID
18292508
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
180
Issue
5
Publish Date
2008
Start Page
2863
End Page
2875

Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase.

Despite the importance of phosphoinositide 3-kinase (PI3K) in B-cell development, its activation mechanism still remains elusive. In this study, we show that deletion of both BCAP and CD19 leads to an almost complete block of BCR-mediated Akt activation and to severe defects in generation of immature and mature B cells. The YXXM motifs in BCAP and CD19 are crucial for regulating B-cell development in that mutation of these motifs abrogated their ability to induce BCR-mediated Akt activation as well as to promote B-cell development. Furthermore, the developmental defect in CD19(-/-)BCAP(-/-) B cells was partly relieved by introducing a constitutively active form of PI3K or PDK1. Together, our data suggest that BCAP and CD19 have complementary roles in BCR-mediated PI3K activation, thereby, at least in part, contributing to B-cell development.

Authors
Aiba, Y; Kameyama, M; Yamazaki, T; Tedder, TF; Kurosaki, T
MLA Citation
Aiba, Y, Kameyama, M, Yamazaki, T, Tedder, TF, and Kurosaki, T. "Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase." Blood 111.3 (February 1, 2008): 1497-1503.
PMID
18025150
Source
pubmed
Published In
Blood
Volume
111
Issue
3
Publish Date
2008
Start Page
1497
End Page
1503
DOI
10.1182/blood-2007-08-109769

CD22 regulates time course of both B cell division and antibody response.

Because pathogens induce infectious symptoms in a time-dependent manner, a rapid immune response is beneficial for defending hosts from pathogens, especially those inducing acute infectious diseases. However, it is largely unknown how the time course of immune responses is regulated. In this study, we demonstrate that B cells deficient in the inhibitory coreceptor CD22 undergo accelerated cell division after Ag stimulation, resulting in rapid generation of plasma cells and Ab production. This finding indicates that CD22 regulates the time course of B cell responses and suggests that CD22 is a good target to shorten the time required for Ab production, thereby augmenting host defense against acute infectious diseases as "universal vaccination."

Authors
Onodera, T; Poe, JC; Tedder, TF; Tsubata, T
MLA Citation
Onodera, T, Poe, JC, Tedder, TF, and Tsubata, T. "CD22 regulates time course of both B cell division and antibody response." J Immunol 180.2 (January 15, 2008): 907-913.
PMID
18178830
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
180
Issue
2
Publish Date
2008
Start Page
907
End Page
913

Dendritic cell CD83: a therapeutic target or innocent bystander?

CD83 represents an intriguing target for immunotherapy due to its preferential expression on mature DCs, the most efficient of antigen presenting cells. Based on its restricted expression pattern, structure, and the paucity of CD4+ T cells in CD83-deficient mice, multiple immunologically important functions for CD83 during immune responses have been proposed. Indeed, several studies have reported that CD83 blockade using soluble receptor constructs inhibits T cell responses in vitro and in vivo, can affect autoimmune disease development and progression, and can inhibit transplant rejection. However, others have not been able to reproduce some of these findings, and antigen presenting cells deficient in CD83 expression or expressing a mutated form of CD83 induce normal T cell responses in vitro. This review examines the controversy surrounding CD83 function, alleged CD83 ligands, the potential therapeutic utility of recombinant proteins targeting CD83 function, and the importance of soluble serum CD83. While the validity of multiple previous studies needs to be confirmed, CD83 remains a fascinating cell surface molecule with a unique pattern of expression that has multiple confirmed functions in regulating immune system development and function.

Authors
Prazma, CM; Tedder, TF
MLA Citation
Prazma, CM, and Tedder, TF. "Dendritic cell CD83: a therapeutic target or innocent bystander?." Immunol Lett 115.1 (January 15, 2008): 1-8. (Review)
PMID
18001846
Source
pubmed
Published In
Immunology Letters
Volume
115
Issue
1
Publish Date
2008
Start Page
1
End Page
8
DOI
10.1016/j.imlet.2007.10.001

Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice.

CD20 mAb-mediated B cell depletion is an effective treatment for B cell malignancies and some autoimmune diseases. However, the full effects of B cell depletion on natural, primary, and secondary Ab responses and the maintenance of Ag-specific serum Ig levels are largely unknown. The relationship between memory B cells, long-lived plasma cells, and long-lived humoral immunity also remains controversial. To address the roles of B cell subsets in the longevity of humoral responses, mature B cells were depleted in mice using CD20 mAb. Peritoneal B cell depletion reduced natural and Ag-induced IgM responses. Otherwise, CD20+ B cell depletion prevented humoral immune responses and class switching and depleted existing and adoptively transferred B cell memory. Nonetheless, B cell depletion did not affect serum Ig levels, Ag-specific Ab titers, or bone marrow Ab-secreting plasma cell numbers. Coblockade of LFA-1 and VLA-4 adhesion molecules temporarily depleted long-lived plasma cells from the bone marrow. CD20+ B cell depletion plus LFA-1/VLA-4 mAb treatment significantly prolonged Ag-specific plasma cell depletion from the bone marrow, with a significant decrease in Ag-specific serum IgG. Collectively, these results support previous claims that bone marrow plasma cells are intrinsically long-lived. Furthermore, these studies now demonstrate that mature and memory B cells are not required for maintaining bone marrow plasma cell numbers, but are required for repopulation of plasma cell-deficient bone marrow. Thereby, depleting mature and memory B cells does not have a dramatic negative effect on preexisting Ab levels.

Authors
DiLillo, DJ; Hamaguchi, Y; Ueda, Y; Yang, K; Uchida, J; Haas, KM; Kelsoe, G; Tedder, TF
MLA Citation
DiLillo, DJ, Hamaguchi, Y, Ueda, Y, Yang, K, Uchida, J, Haas, KM, Kelsoe, G, and Tedder, TF. "Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice." J Immunol 180.1 (January 1, 2008): 361-371.
PMID
18097037
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
180
Issue
1
Publish Date
2008
Start Page
361
End Page
371

Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice.

CD20 antibody depletion of B lymphocytes effectively ameliorates multiple T cell-mediated autoimmune diseases through mechanisms that remain unclear. To address this, a mouse CD20 antibody that depletes >95% of mature B cells in mice with otherwise intact immune systems was used to assess the role of B cells in CD4(+) and CD8(+) T cell activation and expansion in vivo. B cell depletion had no direct effect on T cell subsets or the activation status of CD4(+) and CD8(+) T cells in naive mice. However, B cell depletion impaired CD4(+) T cell activation and clonal expansion in response to protein antigens and pathogen challenge, whereas CD8(+) T cell activation was not affected. In vivo dendritic cell ablation, along with CD20 immunotherapy, revealed that optimal antigen-specific CD4(+) T cell priming required both B cells and dendritic cells. Most importantly, B cell depletion inhibited antigen-specific CD4(+) T cell expansion in both collagen-induced arthritis and autoimmune diabetes mouse models. These results provide direct evidence that B cells contribute to T cell activation and expansion in vivo and offer insights into the mechanism of action for B cell depletion therapy in the treatment of autoimmunity.

Authors
Bouaziz, J-D; Yanaba, K; Venturi, GM; Wang, Y; Tisch, RM; Poe, JC; Tedder, TF
MLA Citation
Bouaziz, J-D, Yanaba, K, Venturi, GM, Wang, Y, Tisch, RM, Poe, JC, and Tedder, TF. "Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice." Proc Natl Acad Sci U S A 104.52 (December 26, 2007): 20878-20883.
PMID
18093919
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
104
Issue
52
Publish Date
2007
Start Page
20878
End Page
20883
DOI
10.1073/pnas.0709205105

Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis.

We have studied the role of CD21/35, which bind derivatives of complement factors C3 and C4, in extraneural prion replication and neuroinvasion. Upon administration of small prion inocula, CD21/35(-/-) mice experienced lower attack rates and delayed disease over both wild-type (WT) mice and mice with combined C3 and C4 deficiencies. Early after inoculation, CD21/35(-/-) spleens were devoid of infectivity. Reciprocal adoptive bone marrow transfers between WT and CD21/35(-/-) mice revealed that protection from prion infection resulted from ablation of stromal, but not hemopoietic, CD21/35. Further adoptive transfer experiments between WT mice and mice devoid of both the cellular prion protein PrP(C) and CD21/35 showed that splenic retention of inoculum depended on stromal CD21/35 expression. Because both PrP(C) and CD21/35 are highly expressed on follicular dendritic cells, CD21/35 appears to be involved in targeting prions to follicular dendritic cells and expediting neuroinvasion following peripheral exposure to prions.

Authors
Zabel, MD; Heikenwalder, M; Prinz, M; Arrighi, I; Schwarz, P; Kranich, J; von Teichman, A; Haas, KM; Zeller, N; Tedder, TF; Weis, JH; Aguzzi, A
MLA Citation
Zabel, MD, Heikenwalder, M, Prinz, M, Arrighi, I, Schwarz, P, Kranich, J, von Teichman, A, Haas, KM, Zeller, N, Tedder, TF, Weis, JH, and Aguzzi, A. "Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis." J Immunol 179.9 (November 1, 2007): 6144-6152.
PMID
17947689
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
179
Issue
9
Publish Date
2007
Start Page
6144
End Page
6152

CD83 expression is a sensitive marker of activation required for B cell and CD4+ T cell longevity in vivo.

CD83 is a surface marker that differentiates immature and mature human dendritic cell populations. Thymic epithelial cell expression of CD83 is also necessary for efficient CD4+ T cell development in mice. The altered phenotypes of peripheral B and CD4+ T cells, and the reduction of peripheral CD4+ T cells in CD83-/- mice, suggest additional functions for CD83. To assess this, a panel of mAbs was generated to characterize mouse CD83 expression by peripheral leukocytes. As in humans, activation of conventional and plasmacytoid murine dendritic cell subsets led to rapid up-regulation of CD83 surface expression in mice. In primary and secondary lymphoid compartments, a subset of B cells expressed low-level CD83, while CD83 was not detected on resting T cells. However, CD83 was prominently up-regulated on the majority of spleen B and T cells within hours of activation in vitro. In vivo, a low dose of hen egg lysozyme (1 microg) induced significant CD83 but not CD69 expression by Ag-specific B cells within 4 h of Ag challenge. Although B cell development appeared normal in CD83-/- mice, B and CD4+ T cell expression of CD83 was required for lymphocyte longevity in adoptive transfer experiments. Thus, the restricted expression pattern of CD83, its rapid induction following B cell and T cell activation, and its requirement for B cell and CD4+ T cell longevity demonstrate that CD83 is a functionally significant and sensitive marker of early lymphocyte activation in vivo.

Authors
Prazma, CM; Yazawa, N; Fujimoto, Y; Fujimoto, M; Tedder, TF
MLA Citation
Prazma, CM, Yazawa, N, Fujimoto, Y, Fujimoto, M, and Tedder, TF. "CD83 expression is a sensitive marker of activation required for B cell and CD4+ T cell longevity in vivo." J Immunol 179.7 (October 1, 2007): 4550-4562.
PMID
17878352
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
179
Issue
7
Publish Date
2007
Start Page
4550
End Page
4562

Endothelial selectins regulate skin wound healing in cooperation with L-selectin and ICAM-1.

Skin wound healing is mediated by inflammatory cell infiltration that is highly regulated by various adhesion molecules. Mice lacking intercellular adhesion molecule-1 (ICAM-1) delayed skin wound healing and mice lacking both L-selectin and ICAM-1 (L-selectin/ICAM-1(-/-)) show more delayed wound healing. Deficiency of both endothelial selectins (E-selectin or P-selectin) also delays wound healing. However, the relative contribution and interaction of selectins and ICAM-1 to the wound healing remain unknown. To clarify them, repair of excisional wounds was examined in L-selectin/ICAM-1(-/-) mice, wild-type mice with both E- and P-selectin blockade, and L-selectin/ICAM-1(-/-) mice with both E- and P-selectin blockade. Wild-type mice with both E- and P-selectin blockade showed delayed wound healing that was comparable with that in L-selectin/ICAM-1(-/-) mice. Combined E- and P-selectin blockade in L-selectin/ICAM-1(-/-) mice resulted in more significant delay. Mice lacking or blocked for adhesion molecules also showed suppressed keratinocyte migration, angiogenesis, granulation tissue formation, leukocyte infiltration, and cytokine expression, including transforming growth factor-beta and interleukin-6. Application of basic fibroblast growth factor (bFGF) but not platelet-derived growth factor to the wounds significantly improved wound healing in L-selectin/ICAM-1(-/-) mice with both E- and P-selectin blockade. bFGF significantly increased the leukocyte infiltration and subsequent fibrogenic cytokine production, as well as keratinocyte migration, angiogenesis, and collagen synthesis despite the loss of four kinds of adhesion molecules. These results indicate that skin wound healing is regulated cooperatively by all selectins and ICAM-1 and may provide critical information for the therapy of skin wounds.

Authors
Yukami, T; Hasegawa, M; Matsushita, Y; Fujita, T; Matsushita, T; Horikawa, M; Komura, K; Yanaba, K; Hamaguchi, Y; Nagaoka, T; Ogawa, F; Fujimoto, M; Steeber, DA; Tedder, TF; Takehara, K; Sato, S
MLA Citation
Yukami, T, Hasegawa, M, Matsushita, Y, Fujita, T, Matsushita, T, Horikawa, M, Komura, K, Yanaba, K, Hamaguchi, Y, Nagaoka, T, Ogawa, F, Fujimoto, M, Steeber, DA, Tedder, TF, Takehara, K, and Sato, S. "Endothelial selectins regulate skin wound healing in cooperation with L-selectin and ICAM-1." J Leukoc Biol 82.3 (September 2007): 519-531.
PMID
17595378
Source
pubmed
Published In
Journal of leukocyte biology
Volume
82
Issue
3
Publish Date
2007
Start Page
519
End Page
531
DOI
10.1189/jlb.0307152

B-lymphocyte depletion ameliorates Sjögren's syndrome in Id3 knockout mice.

Sjögren's syndrome is an autoimmune disease in which immune cells chronically attack the lachrymal and salivary glands. The Id3 knockout mouse is a newly established animal model for primary Sjögren's syndrome. To address the role of B cells in Sjögren's syndrome and autoimmune disease, we studied the effect of CD20 monoclonal antibody treatment on the disease in Id3 knockout mice. Antibody treatment at 2-month intervals led to efficient and sustained B-cell depletion in Id3 knockout mice. A significant improvement of histopathology was observed accompanied by the recovery of saliva secretory function after CD20 antibody treatment. We further show that serum immunoglobulin G3, which is abnormally high in untreated Id3 knockout mice, was reduced after CD20 antibody treatment. This study establishes a new animal model for immunotherapy of Sjögren's symptoms and suggests a possible link between immunoglobulin G3 and disease pathology in Id3 knockout mice.

Authors
Hayakawa, I; Tedder, TF; Zhuang, Y
MLA Citation
Hayakawa, I, Tedder, TF, and Zhuang, Y. "B-lymphocyte depletion ameliorates Sjögren's syndrome in Id3 knockout mice." Immunology 122.1 (September 2007): 73-79.
PMID
17472721
Source
pubmed
Published In
Immunology
Volume
122
Issue
1
Publish Date
2007
Start Page
73
End Page
79
DOI
10.1111/j.1365-2567.2007.02614.x

CD83 influences cell-surface MHC class II expression on B cells and other antigen-presenting cells.

CD83 is a member of the Ig superfamily expressed primarily by mature dendritic cells (DCs). In mice, CD83 expression by thymic stromal cells regulates CD4(+) T cell development, with CD83(-/-) mice demonstrating dramatic reductions in both thymus and peripheral CD4(+) T cells. In this study, CD83 expression was also found to affect MHC class II antigen expression within the thymus and periphery. CD83 deficiency reduced cell-surface class II antigen expression by 25-50% on splenic B cells and DCs, thymic epithelial cells and peritoneal macrophages. Reduced class II expression was a stable and intrinsic property that resulted from increased internalization of class II from the surface of CD83(-/-) B cells. Otherwise, class II antigen transcription, intracellular expression, heterodimer structure, antigen processing and antigen presentation were normal. Reduced class II antigen expression was not the primary cause of the CD83(-/-) phenotype since thymocyte and peripheral T cell development was normal in class II(+/-) mice. Comparable blocks in CD4(+) thymocyte development were also observed in CD83(-/-) and CD83(-/-)class II(+/-) littermates. TCR and CD69 expression patterns in CD83(-/-) mice further suggested that double-positive thymocytes proceed through the class II-dependent stages of positive selection in the absence of CD83. These studies further emphasize a role for CD83 in lymphocyte development and immune regulation and reveal an unexpected role for CD83 expression in influencing cell-surface MHC class II turnover.

Authors
Kuwano, Y; Prazma, CM; Yazawa, N; Watanabe, R; Ishiura, N; Kumanogoh, A; Okochi, H; Tamaki, K; Fujimoto, M; Tedder, TF
MLA Citation
Kuwano, Y, Prazma, CM, Yazawa, N, Watanabe, R, Ishiura, N, Kumanogoh, A, Okochi, H, Tamaki, K, Fujimoto, M, and Tedder, TF. "CD83 influences cell-surface MHC class II expression on B cells and other antigen-presenting cells." Int Immunol 19.8 (August 2007): 977-992.
PMID
17804692
Source
pubmed
Published In
International Immunology
Volume
19
Issue
8
Publish Date
2007
Start Page
977
End Page
992
DOI
10.1093/intimm/dxm067

CD19 expression in B cells is important for suppression of contact hypersensitivity.

Contact hypersensitivity (CHS) is a cutaneous immune reaction mediated mainly by antigen-specific effector T cells and is regarded as a model for Th1/Tc1-mediated inflammation. However, recent reports have suggested pivotal roles of B cells in CHS. CD19 serves as a positive B-cell response regulator that defines signaling thresholds critical for B-cell responses. In the current study, we assessed the role of the B-cell-specific surface molecule CD19 on the development of CHS by examining CD19-deficient mice. Although CD19-deficient mice are hyposensitive to a variety of transmembrane signals, CD19 loss resulted in increased and prolonged reaction of CHS, suggesting an inhibitory role of CD19 expression in CHS. Sensitized lymph nodes and elicited ear lesions from CD19-deficient mice exhibited Th1/Tc1-shifted cytokine profile with increased interferon-gamma expression and decreased interleukin-10 expression. Adoptive transfer experiments revealed that CD19 expression in recipient mice was required for optimal suppression of CHS response, indicating its role in the elicitation phase. Furthermore, spleen B cells, especially marginal zone B cells, from wild-type mice were able to normalize exaggerated CHS reactions in CD19-deficient mice. Thus, CD19 expression in B cells is critical for termination of CHS responses, possibly through the function of regulatory B cells.

Authors
Watanabe, R; Fujimoto, M; Ishiura, N; Kuwano, Y; Nakashima, H; Yazawa, N; Okochi, H; Sato, S; Tedder, TF; Tamaki, K
MLA Citation
Watanabe, R, Fujimoto, M, Ishiura, N, Kuwano, Y, Nakashima, H, Yazawa, N, Okochi, H, Sato, S, Tedder, TF, and Tamaki, K. "CD19 expression in B cells is important for suppression of contact hypersensitivity." Am J Pathol 171.2 (August 2007): 560-570.
PMID
17556590
Source
pubmed
Published In
The American journal of pathology
Volume
171
Issue
2
Publish Date
2007
Start Page
560
End Page
570
DOI
10.2353/ajpath.2007.061279

B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires synergy between humoral and cell-mediated immunity.

Rheumatoid arthritis is a systemic autoimmune disease. B cells are likely to play a critical role in arthritis pathogenesis, although it is unclear whether they are necessary for disease induction, autoantibody production, or disease progression. To assess the role of B cells in inflammatory arthritis, B cells were depleted using mouse anti-mouse CD20 mAbs in a mouse model of collagen-induced arthritis. CD20 mAbs effectively depleted mature B cells from adult DBA-1 mice. When B cells were depleted using CD20 mAbs before collagen immunization, there was a delay in disease onset and autoantibody production, with significantly diminished severity of arthritis both clinically and histologically. B cell depletion further delayed disease onset if initiated before, as well as after, collagen immunization. However, in both cases, the eventual reappearance of peripheral B cells triggered autoantibody production and the subsequent development of arthritis in collagen-sensitized mice. By contrast, B cell depletion after collagen immunizations did not have a significant effect on arthritis progression or severity. Thus, disease symptoms were only induced when peripheral B cells and their autoantibody products were present in collagen-immunized mice, documenting a critical role for B cells during the elicitation phase of collagen-induced arthritis. These studies suggest that B cell depletion strategies will be most effective when initiated early in the development of inflammatory arthritis, with sustained B cell depletion required to inhibit the production of isotype-switched pathogenic Abs and the evolution of joint inflammation and destruction.

Authors
Yanaba, K; Hamaguchi, Y; Venturi, GM; Steeber, DA; St Clair, EW; Tedder, TF
MLA Citation
Yanaba, K, Hamaguchi, Y, Venturi, GM, Steeber, DA, St Clair, EW, and Tedder, TF. "B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires synergy between humoral and cell-mediated immunity." J Immunol 179.2 (July 15, 2007): 1369-1380.
PMID
17617630
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
179
Issue
2
Publish Date
2007
Start Page
1369
End Page
1380

Intercellular adhesion molecule-1 deficiency attenuates the development of skin fibrosis in tight-skin mice.

The tight-skin (TSK/+) mouse, a genetic model for systemic sclerosis, develops cutaneous fibrosis. Although a fibrillin 1 gene mutation and immunological abnormalities have been demonstrated, the roles of adhesion molecules have not been investigated. To directly assess roles of adhesion molecules in skin fibrosis, TSK/+ mice lacking L-selectin and/or ICAM-1 were generated. The deficiency of ICAM-1, but not L-selectin, significantly suppressed ( approximately 48%) the development of skin sclerosis in TSK/+ mice. Similarly, ICAM-1 antisense oligonucleotides inhibited skin fibrosis in TSK/+ mice. Although T cell infiltration was modest into the skin of TSK/+ mice, ICAM-1 deficiency down-regulated this migration, which is consistent with the established roles of endothelial ICAM-1 in leukocyte infiltration. In addition, altered phenotype or function of skin fibroblasts was remarkable and dependent on ICAM-1 expression in TSK/+ mice. ICAM-1 expression was augmented on TSK/+ dermal fibroblasts stimulated with IL-4. Although growth or collagen synthesis of TSK/+ fibroblasts cultured with IL-4 was up-regulated, it was suppressed by the loss or blocking of ICAM-1. Collagen expression was dependent on the strain of fibroblasts, but not on the strain of cocultured T cells. Thus, our findings indicate that ICAM-1 expression contributes to the development of skin fibrosis in TSK/+ mice, especially via ICAM-1 expressed on skin fibroblasts.

Authors
Matsushita, Y; Hasegawa, M; Matsushita, T; Fujimoto, M; Horikawa, M; Fujita, T; Kawasuji, A; Ogawa, F; Steeber, DA; Tedder, TF; Takehara, K; Sato, S
MLA Citation
Matsushita, Y, Hasegawa, M, Matsushita, T, Fujimoto, M, Horikawa, M, Fujita, T, Kawasuji, A, Ogawa, F, Steeber, DA, Tedder, TF, Takehara, K, and Sato, S. "Intercellular adhesion molecule-1 deficiency attenuates the development of skin fibrosis in tight-skin mice." J Immunol 179.1 (July 1, 2007): 698-707.
PMID
17579093
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
179
Issue
1
Publish Date
2007
Start Page
698
End Page
707

CD25+CD4+ regulatory T cell migration requires L-selectin expression: L-selectin transcriptional regulation balances constitutive receptor turnover.

The molecular mechanisms controlling regulatory CD25(+)Foxp3(+)CD4(+) T cell (T(reg)) migration are central to in vivo immune responses. T(reg) cell subsets differentially express L-selectin, an adhesion molecule mediating lymphocyte migration to peripheral LNs (PLNs) and leukocyte rolling during inflammation. In this study, L-selectin was essential for T(reg) cell migration and normal tissue distribution. Specifically, there was a 90% reduction in PLN T(reg) cells in L-selectin(-/-) mice with a compensatory increase in spleen T(reg) cell numbers. Unexpectedly, however, 40% of the CD4(+) T cells remaining within PLNs of L-selectin(-/-) mice were T(reg) cells. The migratory properties of T(reg) cells were nonetheless markedly different from those of naive CD4(+) T cells, with 3- to 9-fold lower migration of T(reg) cells into PLNs and approximately 2-fold lower migration into the spleen. T(reg) cells also turned over cell surface L-selectin at a faster rate than CD25(-)CD4(+) T cells, but maintained physiologically appropriate L-selectin densities for optimal migration. Specifically, T(reg) cells expressed 30-40% more cell surface L-selectin when its endoproteolytic cleavage was blocked genetically, which resulted in a 2-fold increase in T(reg) cell migration into PLNs. However, increased L-selectin cleavage by T(reg) cells in wild-type mice was accompanied by 2-fold higher L-selectin mRNA levels, which resulted in equivalent cell surface L-selectin densities on T(reg) and naive T cells. Thus, T(reg) cells and CD25(-)CD4(+) T cells share similar requirements for L-selectin expression during migration, although additional molecular mechanisms constrain T(reg) cell migration beyond what is required for naive CD4(+) T cell migration.

Authors
Venturi, GM; Conway, RM; Steeber, DA; Tedder, TF
MLA Citation
Venturi, GM, Conway, RM, Steeber, DA, and Tedder, TF. "CD25+CD4+ regulatory T cell migration requires L-selectin expression: L-selectin transcriptional regulation balances constitutive receptor turnover." J Immunol 178.1 (January 1, 2007): 291-300.
PMID
17182566
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
178
Issue
1
Publish Date
2007
Start Page
291
End Page
300

CD19 hyperexpression augments Sle1 -induced humoral autoimmunity but not clinical nephritis

Objective. B cell hyperactivity is a common denominator in murine and human systemic lupus erythematosus. Some susceptibility genes in lupus are associated with B cell hyperactivity, but others are clearly not. While the Sle1 lupus susceptibility locus of NZM2410/NZW origin leads to chromatin-focused autoimmunity, genetically engineered overexpression of CD19 leads to "generalized" B cell hyperactivity. We undertook this study to determine the degree to which generalized B cell hyperactivity can amplify lupus pathogenesis. Methods. To elucidate the impact of generalized B cell hyperactivity on Sle1 -triggered autoimmunity, B6 mice bearing the human CD19 transgene were rendered congenic for the Sle1z genetic locus and phenotyped for serologic, cellular, and pathologic evidence of lupus. Results. As expected, B6.Sle1.hCD19Tg/Tg mice, homozygous at Sle1 and bearing the hCD19 transgene, exhibited high levels of IgM and IgG anti-DNA/ antiglomerular autoantibodies, skewed B cell subsets, and profoundly activated B and T cells. Despite exhibiting glomerular IgM, IgG, and complement deposits, these mice did not exhibit accelerated mortality or any clinical evidence of renal dysfunction. Conclusion. Generalized B cell hyperactivity may augment humoral autoimmunity, but this may not suffice to engender end-organ disease in lupus. These findings allude to the presence of an additional distal checkpoint that dissociates pathogenic autoantibody formation and renal immunoglobulin deposition from the progression to clinical nephritis in lupus. © 2007. American College of Rheumatology.

Authors
Shi, X; Xie, C; Chang, S; Zhou, XJ; Tedder, T; Mohan, C
MLA Citation
Shi, X, Xie, C, Chang, S, Zhou, XJ, Tedder, T, and Mohan, C. "CD19 hyperexpression augments Sle1 -induced humoral autoimmunity but not clinical nephritis." Arthritis and Rheumatism 56.9 (2007): 3057-3069.
PMID
17763445
Source
scival
Published In
Arthritis and Rheumatism
Volume
56
Issue
9
Publish Date
2007
Start Page
3057
End Page
3069
DOI
10.1002/art.22825

Fcgamma receptor-dependent effector mechanisms regulate CD19 and CD20 antibody immunotherapies for B lymphocyte malignancies and autoimmunity.

Immunotherapy using Rituximab, an unconjugated CD20 monoclonal antibody, has proven effective for treating non-Hodgkin's lymphoma and autoimmune disease. CD19 antibody immunotherapy is also effective in mouse models of lymphoma and autoimmunity. In both cases, mouse models have demonstrated that effector cell networks effectively deplete the vast majority of circulating and tissue B lymphocytes through Fcgamma receptor-dependent pathways. In mice, B cell depletion is predominantly, if not exclusively, mediated by monocytes. CD20 mAbs rapidly deplete circulating and tissue B cells in an antibody isotype-restricted manner with a hierarchy of antibody effectiveness: IgG2a/c > IgG1 > IgG2b > IgG3. Depending on antibody isotype, mouse B cell depletion is regulated by FcgammaRI-, FcgammaRII-, FcgammaRIII-, and FcgammaRIV-dependent pathways. The potency of IgG2a/c mAbs for B cell depletion in vivo results from FcgammaRIV interactions, with likely contributions from high-affinity FcgammaRI. IgG1 mAbs induce B cell depletion through preferential, if not exclusive, interactions with low-affinity FcgammaRIII, while IgG2b mAbs interact preferentially with intermediate-affinity FcgammaRIV. By contrast, inhibitory FcgammaRIIB-deficiency significantly increases CD20 mAb-induced B cell depletion at low mAb doses by enhancing monocyte function. Thus, isotype-specific mAb interactions with distinct FcgammaRs contribute significantly to the effectiveness of CD20 mAbs in vivo. These results provide a molecular basis for earlier observations that human FcgammaRII and FcgammaRIII polymorphisms correlate with the in vivo effectiveness of CD20 antibody therapy. That the innate monocyte network depletes B cells through FcgammaR-dependent pathways during immunotherapy has important clinical implications for CD19, CD20, and other antibody-based therapies for the treatment of diverse B cell malignancies and autoimmune disease.

Authors
Tedder, TF; Baras, A; Xiu, Y
MLA Citation
Tedder, TF, Baras, A, and Xiu, Y. "Fcgamma receptor-dependent effector mechanisms regulate CD19 and CD20 antibody immunotherapies for B lymphocyte malignancies and autoimmunity." Springer Semin Immunopathol 28.4 (December 2006): 351-364.
PMID
17091246
Source
pubmed
Published In
Springer seminars in immunopathology
Volume
28
Issue
4
Publish Date
2006
Start Page
351
End Page
364
DOI
10.1007/s00281-006-0057-9

Decreased expression levels of CD22 and L-selectin on peripheral blood B lymphocytes from patients with bullous pemphigoid.

Bullous pemphigoid (BP), an autoimmune subepidermal-blistering disease of the elderly, is caused by antibodies against BP antigens at the epidermal basement membrane zone (BMZ). CD22 is a B lymphocyte specific response regulator, which is down-regulated after B-cell activation. Old CD22-deficient mice produce class-switched autoantibodies. To assess the role of CD22 in the pathogenesis of BP, we examined CD22 expression on B cells from BP patients and correlated its expression with clinical parameters. B cell expression of CD22 was 20% lower in BP patients when compared to healthy control subjects. In addition, B cells from BP patients showed decreased expression of L-selectin, which is an indicator of leukocyte activation, and CD22 expression levels were correlated with L-selectin expression. These results suggest that the decreased CD22 expression may be associated with the activation of B cells in BP. CD22 expression levels in BP patients did not correlate with the levels of anti-epidermal BMZ antibodies, and old CD22-deficient mice did not develop the anti-epidermal BMZ antibody. These results suggest that a decrease in CD22 expression may not be associated with BP-specific antibody production.

Authors
Inaoki, M; Echigo, T; Hayashi, H; Nagaoka, T; Hasegawa, M; Takehara, K; Fujimoto, W; Tedder, TF; Sato, S
MLA Citation
Inaoki, M, Echigo, T, Hayashi, H, Nagaoka, T, Hasegawa, M, Takehara, K, Fujimoto, W, Tedder, TF, and Sato, S. "Decreased expression levels of CD22 and L-selectin on peripheral blood B lymphocytes from patients with bullous pemphigoid." J Autoimmun 27.3 (November 2006): 196-202.
PMID
17055225
Source
pubmed
Published In
Journal of Autoimmunity
Volume
27
Issue
3
Publish Date
2006
Start Page
196
End Page
202
DOI
10.1016/j.jaut.2006.09.002

CD22 ligand binding regulates normal and malignant B lymphocyte survival in vivo.

The CD22 extracellular domain regulates B lymphocyte function by interacting with alpha2,6-linked sialic acid-bearing ligands. To understand how CD22 ligand interactions affect B cell function in vivo, mouse anti-mouse CD22 mAbs were generated that inhibit CD22 ligand binding to varying degrees. Remarkably, mAbs which blocked CD22 ligand binding accelerated mature B cell turnover by 2- to 4-fold in blood, spleen, and lymph nodes. CD22 ligand-blocking mAbs also inhibited the survival of adoptively transferred normal (73-88%) and malignant (90%) B cells in vivo. Moreover, mAbs that bound CD22 ligand binding domains induced significant CD22 internalization, depleted marginal zone B cells (82-99%), and reduced mature recirculating B cell numbers by 75-85%. The CD22 mAb effects were independent of complement and FcRs, and the CD22 mAbs had minimal effects in CD22AA mice that express mutated CD22 that is not capable of ligand binding. These data demonstrate that inhibition of CD22 ligand binding can disrupt normal and malignant B cell survival in vivo and suggest a novel mechanism of action for therapeutics targeting CD22 ligand binding domains.

Authors
Haas, KM; Sen, S; Sanford, IG; Miller, AS; Poe, JC; Tedder, TF
MLA Citation
Haas, KM, Sen, S, Sanford, IG, Miller, AS, Poe, JC, and Tedder, TF. "CD22 ligand binding regulates normal and malignant B lymphocyte survival in vivo." J Immunol 177.5 (September 1, 2006): 3063-3073.
PMID
16920943
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
177
Issue
5
Publish Date
2006
Start Page
3063
End Page
3073

B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis.

Systemic sclerosis (scleroderma) is an autoimmune disease characterized by excessive extracellular matrix deposition in the skin. A direct role for B lymphocytes in disease development or progression has remained controversial, although autoantibody production is a feature of this disease. To address this issue, skin sclerosis and autoimmunity were assessed in tight-skin mice, a genetic model of human systemic sclerosis, after circulating and tissue B-cell depletion using an anti-mouse CD20 monoclonal antibody before (day 3 after birth) and after disease development (day 56). CD20 monoclonal antibody treatment (10 to 20 microg) depleted the majority (85 to 99%) of circulating and tissue B cells in newborn and adult tight-skin mice by days 56 and 112, respectively. B-cell depletion in newborn tight-skin mice significantly suppressed (approximately 43%) the development of skin fibrosis, autoantibody production, and hypergammaglobulinemia. B-cell depletion also restored a more normal balance between Th1 and Th2 cytokine mRNA expression in the skin. By contrast, B-cell depletion did not affect skin fibrosis, hypergammaglobulinemia, and autoantibody levels in adult mice with established disease. Thereby, B-cell depletion during disease onset suppressed skin fibrosis, indicating that B cells contribute to the initiation of systemic sclerosis pathogenesis in tight-skin mice but are not required for disease maintenance.

Authors
Hasegawa, M; Hamaguchi, Y; Yanaba, K; Bouaziz, J-D; Uchida, J; Fujimoto, M; Matsushita, T; Matsushita, Y; Horikawa, M; Komura, K; Takehara, K; Sato, S; Tedder, TF
MLA Citation
Hasegawa, M, Hamaguchi, Y, Yanaba, K, Bouaziz, J-D, Uchida, J, Fujimoto, M, Matsushita, T, Matsushita, Y, Horikawa, M, Komura, K, Takehara, K, Sato, S, and Tedder, TF. "B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis." Am J Pathol 169.3 (September 2006): 954-966.
PMID
16936269
Source
pubmed
Published In
The American journal of pathology
Volume
169
Issue
3
Publish Date
2006
Start Page
954
End Page
966
DOI
10.2353/ajpath.2006.060205

CD83: a regulatory molecule of the immune system with great potential for therapeutic application.

CD83 has been known for a decade to be one of the best markers for mature dendritic cells (DCs). The recognition of CD83 was greatly changed since CD83 in thymus was unveiled to be essential for the generation of CD4+ T cells by the study using CD83-deficient mice. It was recently shown that both activated DCs and B cells release soluble form of CD83 and that low levels of soluble CD83 are present in normal human sera. Both in vivo and in vitro studies demonstrated that soluble CD83 has immunosuppressive roles such as the inhibition of DC-mediated T cell stimulation and the maturation of DCs. CD83 appears to have regulatory functions for immune response in light of observations that the soluble form of CD83 can inhibits immune reactions while being strongly up-regulated during DC maturation and activation. In addition, the fact that various cell types including thymic epithelial cells, activated T and B cells and activated DCs express CD83 suggests the universal role in immune function. Because of these immuno-regulatory functions, the therapeutic application of CD83 is highly anticipated in many pathological states including malignancy and autoimmune disease.

Authors
Fujimoto, Y; Tedder, TF
MLA Citation
Fujimoto, Y, and Tedder, TF. "CD83: a regulatory molecule of the immune system with great potential for therapeutic application." J Med Dent Sci 53.2 (June 2006): 85-91. (Review)
PMID
16913569
Source
pubmed
Published In
Journal of medical and dental sciences
Volume
53
Issue
2
Publish Date
2006
Start Page
85
End Page
91

Immunotherapy of B-cell malignancies with genetically engineered human CD8+ natural killer T cells.

Authors
Pieper, M; Scheffold, C; Duwe, S; Rossig, C; Bisping, G; Stelljes, M; Tedder, TF; Jurgens, H; Berdel, WE; Kienast, J
MLA Citation
Pieper, M, Scheffold, C, Duwe, S, Rossig, C, Bisping, G, Stelljes, M, Tedder, TF, Jurgens, H, Berdel, WE, and Kienast, J. "Immunotherapy of B-cell malignancies with genetically engineered human CD8+ natural killer T cells." Leukemia 20.4 (April 2006): 729-732. (Letter)
PMID
16437143
Source
pubmed
Published In
Leukemia
Volume
20
Issue
4
Publish Date
2006
Start Page
729
End Page
732
DOI
10.1038/sj.leu.2404114

L-selectin and intercellular adhesion molecule-1 regulate the development of Concanavalin A-induced liver injury.

Concanavalin A (Con A)-induced hepatitis is a model for human T cell-mediated hepatitis. We evaluated the role of L-selectin and intercellular adhesion molecule-1 (ICAM-1) in this model by injecting Con A intravenously in mice lacking L-selectin (L-selectin-/-), ICAM-1 (ICAM-1-/-), or both (L-selectin/ICAM-1-/-). Blood and liver samples were collected 0, 8, 24, and 48 h after Con A treatment. Increases in plasma transaminase levels, which peaked 8 h after injection, were reduced significantly in L-selectin-/-, ICAM-1-/-, and L-selectin/ICAM-1-/- mice compared with wild-type mice. Liver necrosis was more strongly inhibited in ICAM-1-/- mice than in L-selectin-/- mice but was most prominently reduced in L-selectin/ICAM-1-/- mice, in parallel with decreased plasma transaminase levels. The reduced severity of hepatitis in the mutant mice correlated with decreases in numbers of liver CD4+ T cells but not numbers of CD8+ T cells or neutrophils. Following Con A treatment, L-selectin deficiency reduced liver mRNA expression of tumor necrosis factor-alpha, and ICAM-1 deficiency reduced expression of interleukin-4. By contrast, reductions in liver macrophage inhibitor protein-1alpha mRNA occurred in all mutant mice. These results indicate that L-selectin and ICAM-1 contribute cooperatively to the development of Con A-induced hepatitis by regulating leukocyte infiltration and subsequent cytokine production.

Authors
Kawasuji, A; Hasegawa, M; Horikawa, M; Fujita, T; Matsushita, Y; Matsushita, T; Fujimoto, M; Steeber, DA; Tedder, TF; Takehara, K; Sato, S
MLA Citation
Kawasuji, A, Hasegawa, M, Horikawa, M, Fujita, T, Matsushita, Y, Matsushita, T, Fujimoto, M, Steeber, DA, Tedder, TF, Takehara, K, and Sato, S. "L-selectin and intercellular adhesion molecule-1 regulate the development of Concanavalin A-induced liver injury." J Leukoc Biol 79.4 (April 2006): 696-705.
PMID
16461740
Source
pubmed
Published In
Journal of leukocyte biology
Volume
79
Issue
4
Publish Date
2006
Start Page
696
End Page
705
DOI
10.1189/jlb.0905527

Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy.

CD20 monoclonal antibody (mAb) immunotherapy is effective for lymphoma and autoimmune disease. In a mouse model of immunotherapy using mouse anti-mouse CD20 mAbs, the innate monocyte network depletes B cells through immunoglobulin (Ig)G Fc receptor (FcgammaR)-dependent pathways with a hierarchy of IgG2a/c>IgG1/IgG2b>IgG3. To understand the molecular basis for these CD20 mAb subclass differences, B cell depletion was assessed in mice deficient or blocked for stimulatory FcgammaRI, FcgammaRIII, FcgammaRIV, or FcR common gamma chain, or inhibitory FcgammaRIIB. IgG1 CD20 mAbs induced B cell depletion through preferential, if not exclusive, interactions with low-affinity FcgammaRIII. IgG2b CD20 mAbs interacted preferentially with intermediate affinity FcgammaRIV. The potency of IgG2a/c CD20 mAbs resulted from FcgammaRIV interactions, with potential contributions from high-affinity FcgammaRI. Regardless, FcgammaRIV could mediate IgG2a/b/c CD20 mAb-induced depletion in the absence of FcgammaRI and FcgammaRIII. In contrast, inhibitory FcgammaRIIB deficiency significantly increased CD20 mAb-induced B cell depletion by enhancing monocyte function. Although FcgammaR-dependent pathways regulated B cell depletion from lymphoid tissues, both FcgammaR-dependent and -independent pathways contributed to mature bone marrow and circulating B cell clearance by CD20 mAbs. Thus, isotype-specific mAb interactions with distinct FcgammaRs contribute significantly to the effectiveness of CD20 mAbs in vivo, which may have important clinical implications for CD20 and other mAb-based therapies.

Authors
Hamaguchi, Y; Xiu, Y; Komura, K; Nimmerjahn, F; Tedder, TF
MLA Citation
Hamaguchi, Y, Xiu, Y, Komura, K, Nimmerjahn, F, and Tedder, TF. "Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy." J Exp Med 203.3 (March 20, 2006): 743-753.
PMID
16520392
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
203
Issue
3
Publish Date
2006
Start Page
743
End Page
753
DOI
10.1084/jem.20052283

Inhibitory role of CD19 in the progression of experimental autoimmune encephalomyelitis by regulating cytokine response.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nerve system that is considered a T helper type 1 (Th1)-mediated autoimmune disease. EAE currently serves as an experimental animal model for multiple sclerosis in human. Cytokines, such as interferon-gamma and interleukin-10, play a key role in the development and remission of EAE. Recent studies have also shown a role for B cells in the pathogenesis of EAE. Therefore, we examined the role of CD19, a B cell-specific surface molecule that defines signaling thresholds critical for B-cell responses and autoimmunity, on the development of EAE. Following immunization with myelin oligodendrocyte glycoprotein (MOG) peptide, CD19-deficient (CD19(-/-)) mice exhibited higher clinical and pathological severity scores of EAE than wild-type mice. The increased severity of EAE in CD19(-/-) mice was associated with polarized Th1 cytokines in the inflamed central nerve system but not with anti-MOG antibodies in the serum. MOG-primed CD19(-/-) B cells produced high levels of interferon-gamma, and transfer of MOG-primed CD19(-/-) B cells to wild-type mice worsened the disease. Thus, CD19 modulates the Th1/Th2 cytokine balance in B cells and plays a critical role as a suppressive molecule in the development of EAE.

Authors
Matsushita, T; Fujimoto, M; Hasegawa, M; Komura, K; Takehara, K; Tedder, TF; Sato, S
MLA Citation
Matsushita, T, Fujimoto, M, Hasegawa, M, Komura, K, Takehara, K, Tedder, TF, and Sato, S. "Inhibitory role of CD19 in the progression of experimental autoimmune encephalomyelitis by regulating cytokine response." Am J Pathol 168.3 (March 2006): 812-821.
PMID
16507897
Source
pubmed
Published In
The American journal of pathology
Volume
168
Issue
3
Publish Date
2006
Start Page
812
End Page
821
DOI
10.2353/ajpath.2006.050923

Regulation of local and metastatic host-mediated anti-tumour mechanisms by L-selectin and intercellular adhesion molecule-1.

Malignant melanoma is often accompanied by a host response of inflammatory cell infiltration that is highly regulated by multiple adhesion molecules. To assess the role of adhesion molecules, including L-selectin and intercellular adhesion molecule-1 (ICAM-1), in this process, subcutaneous primary growth and metastasis to the lung of B16 melanoma cells not expressing L-selectin, ICAM-1 or their ligands were examined in mice lacking L-selectin, ICAM-1 or both. Primary subcutaneous growth of B16 melanoma was augmented by loss of L-selectin, ICAM-1 or both, while pulmonary metastasis was enhanced by the loss of L-selectin or combined loss of L-selectin and ICAM-1. In both situations, the combined loss of L-selectin and ICAM-1 exhibited the greatest effect. This enhancement was associated generally with a reduced accumulation of natural killer (NK) cells, CD4+ T cells and CD8+ T cells and also with a diminished release of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha but not interleukin (IL)-6. Cytotoxicity against melanoma was not defective by the absence of ICAM-1, L-selectin or both, suggesting that the enhancement of tumour growth and metastasis caused by the loss of adhesion molecules results from an impaired migration of effector cells into the tissue rather than from a suppression of the cytotoxic response. The results indicate that L-selectin and ICAM-1 contribute co-operatively to the anti-tumour reaction by regulating lymphocyte infiltration to the tumour.

Authors
Yamada, M; Yanaba, K; Hasegawa, M; Matsushita, Y; Horikawa, M; Komura, K; Matsushita, T; Kawasuji, A; Fujita, T; Takehara, K; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Yamada, M, Yanaba, K, Hasegawa, M, Matsushita, Y, Horikawa, M, Komura, K, Matsushita, T, Kawasuji, A, Fujita, T, Takehara, K, Steeber, DA, Tedder, TF, and Sato, S. "Regulation of local and metastatic host-mediated anti-tumour mechanisms by L-selectin and intercellular adhesion molecule-1." Clin Exp Immunol 143.2 (February 2006): 216-227.
PMID
16412045
Source
pubmed
Published In
Clinical & Experimental Immunology
Volume
143
Issue
2
Publish Date
2006
Start Page
216
End Page
227
DOI
10.1111/j.1365-2249.2005.02989.x

Improved antigen binding by a CD20-specific single-chain antibody fragment with a mutation in CDRH1.

We have prepared single-chain immunoglobulin Fv fragments from the CD20-specific hybridoma HB13d. One scFv clone demonstrated strong binding to a CD20-derived peptide by ELISA and to CD20-positive cells by flow cytometry, a second had reduced binding, and a third clone did not bind the target antigen. Sequence analysis showed that all three constructs contained shared and unique amino acid changes when compared to the nearest germline match. Molecular modelling of the scFv variants revealed that several of the mutations are located in regions predicted to contact antigen, including a mutation in the heavy chain CDR1 of the strongest binding scFv construct. No similar mutation is present in the highly conserved protein sequences of a number of CD20-specific monoclonal antibodies. BIACORE analysis demonstrated that the mutated scFv had approximately three-fold greater antigen-binding activity than another clone. Competition studies showed that the scFv is able to compete with intact CD20 monoclonal antibody for binding to the target antigen. The improved antigen binding of this scFv will permit the construction of novel CD20-specific reagents for the therapy of lymphomas.

Authors
Adamson, PJ; Millard, DJ; Hohmann, AW; Mavrangelos, C; Macardle, PJ; Pilkington, G; Mulhern, TD; Tedder, TF; Zola, H; Nicholson, IC
MLA Citation
Adamson, PJ, Millard, DJ, Hohmann, AW, Mavrangelos, C, Macardle, PJ, Pilkington, G, Mulhern, TD, Tedder, TF, Zola, H, and Nicholson, IC. "Improved antigen binding by a CD20-specific single-chain antibody fragment with a mutation in CDRH1." Mol Immunol 43.6 (February 2006): 550-558.
PMID
15936081
Source
pubmed
Published In
Molecular Immunology
Volume
43
Issue
6
Publish Date
2006
Start Page
550
End Page
558
DOI
10.1016/j.molimm.2005.04.016

B cell antigen receptor and CD40 differentially regulate CD22 tyrosine phosphorylation.

Cell surface molecules on lymphocytes positively or negatively modulate the Ag receptor signaling, and thus regulate the fate of the cell. CD22 is a B cell-specific cell surface protein that contains multiple ITIMs in the cytoplasmic tail, and critically regulates B cell activation and survival. CD22 regulation on B cell signaling is complex because CD22 can have both positive and negative roles in various contexts. We generated phosphospecific polyclonal Abs reacting four major CD22 tyrosine motifs (Y762, Y807, Y822, and Y842) and analyzed the pattern and intensity of phosphorylation of these tyrosine residues. The tyrosine motifs, Y762, Y822, and Y842, are considered as ITIM, whereas the other, Y807, is suggested to be important for Grb2 recruitment. Approximately 10% of the four tyrosine residues were constitutively phosphorylated. Upon anti-IgM ligation, CD22 Y762 underwent most rapid phosphorylation, whereas all four tyrosine residues were eventually phosphorylated equally at approximately 35% of all CD22 molecules in the cell. By contrast, anti-CD40 stimulation specifically up-regulated anti-IgM-induced phosphorylation of tyrosines within two ITIM motifs, Y762 and Y842, which was consistent with in vivo finding of the negative role of CD22 in CD40 signaling. Thus, CD22 phosphorylation is not only quantitatively but also qualitatively regulated by different stimulations, which may determine the outcome of B cell signaling.

Authors
Fujimoto, M; Kuwano, Y; Watanabe, R; Asashima, N; Nakashima, H; Yoshitake, S; Okochi, H; Tamaki, K; Poe, JC; Tedder, TF; Sato, S
MLA Citation
Fujimoto, M, Kuwano, Y, Watanabe, R, Asashima, N, Nakashima, H, Yoshitake, S, Okochi, H, Tamaki, K, Poe, JC, Tedder, TF, and Sato, S. "B cell antigen receptor and CD40 differentially regulate CD22 tyrosine phosphorylation." J Immunol 176.2 (January 15, 2006): 873-879.
PMID
16393971
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
176
Issue
2
Publish Date
2006
Start Page
873
End Page
879

New prospects for autoimmune disease therapy: B cells on deathwatch.

Authors
St Clair, EW; Tedder, TF
MLA Citation
St Clair, EW, and Tedder, TF. "New prospects for autoimmune disease therapy: B cells on deathwatch." Arthritis Rheum 54.1 (January 2006): 1-9. (Review)
PMID
16385491
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
54
Issue
1
Publish Date
2006
Start Page
1
End Page
9
DOI
10.1002/art.21525

Reply [7]

Authors
Tedder, TF; Clair, EWS
MLA Citation
Tedder, TF, and Clair, EWS. "Reply [7]." Arthritis and Rheumatism 54.7 (2006): 2344-2345.
Source
scival
Published In
Arthritis and Rheumatism
Volume
54
Issue
7
Publish Date
2006
Start Page
2344
End Page
2345
DOI
10.1002/art.21938

Loss of tolerance of anti-dsDNA B cells in mice overexpressing CD19

Mice transgenic for the R4A-Cμ heavy chain of an anti-dsDNA antibody, maintain tolerance by anergy and deletion. In C57BL/6 mice overexpressing CD19, a molecule, which lowers the threshold for B cell activation, elevated levels of serum autoantibodies have been observed. In the present study, we wished to determine whether CD19 overexpression could alter the induction of tolerance in R4A-Cμ mice and lead to the secretion of transgenic anti-dsDNA antibodies. We, therefore, bred R4A-Cμ transgenic mice-to-mice transgenic for human CD19 (hCD19) and generated R4A-Cμ mice heterozygous and homozygous for hCD19. We, now report the spontaneous secretion of transgenic IgM anti-dsDNA antibody in the sera of R4A-Cμ mice overexpressing CD19, indicative of a loss of B cell tolerance. We observe that transgenic B cells secreting anti-dsDNA antibody in these mice are T independent and display a marginal zone like phenotype althought they do not reside in the MZ. In addition, they appear to be derived from the conventional B2 subset rather than the B1 subset. Interestingly, a subset of the anti-dsDNA B cells in these mice still display the phenotype and functional characteristics of anergic B cells. These B cells cannot be activated to secrete antibody following BCR crosslinking, however, they are hyper-responsive to activation by innate signaling mechanisms. This suggests that CD19 overexpression may promote anergic B cells to escape tolerance by converging with BCR independent pathways, thereby rendering these B cells hyper-responsive to innate signaling. © 2005 Elsevier Ltd. All rights reserved.

Authors
Taylor, DK; Ito, E; Thorn, M; Sundar, K; Tedder, T; Spatz, LA
MLA Citation
Taylor, DK, Ito, E, Thorn, M, Sundar, K, Tedder, T, and Spatz, LA. "Loss of tolerance of anti-dsDNA B cells in mice overexpressing CD19." Molecular Immunology 43.11 (2006): 1776-1790.
PMID
16430962
Source
scival
Published In
Molecular Immunology
Volume
43
Issue
11
Publish Date
2006
Start Page
1776
End Page
1790
DOI
10.1016/j.molimm.2005.11.003

Complement component C3d-antigen complexes can either augment or inhibit B lymphocyte activation and humoral immunity in mice depending on the degree of CD21/CD19 complex engagement.

C3d can function as a molecular adjuvant by binding CD21 and thereby enhancing B cell activation and humoral immune responses. However, recent studies suggest both positive and negative roles for C3d and the CD19/CD21 signaling complex in regulating humoral immunity. To address whether signaling through the CD19/CD21 complex can negatively regulate B cell function when engaged by physiological ligands, diphtheria toxin (DT)-C3d fusion protein and C3dg-streptavidin (SA) complexes were used to assess the role of CD21 during BCR-induced activation and in vivo immune responses. Immunization of mice with DT-C3d3 significantly reduced DT-specific Ab responses independently of CD21 expression or signaling. By contrast, SA-C3dg tetramers dramatically enhanced anti-SA responses when used at low doses, whereas 10-fold higher doses did not augment immune responses, except in CD21/35-deficient mice. Likewise, SA-C3dg (1 microg/ml) dramatically enhanced BCR-induced intracellular calcium concentration ([Ca2+]i) responses in vitro, but had no effect or inhibited [Ca2+]i responses when used at 10- to 50-fold higher concentrations. SA-C3dg enhancement of BCR-induced [Ca2+]i responses required CD21 and CD19 expression and resulted in significantly enhanced CD19 and Lyn phosphorylation, with enhanced Lyn/CD19 associations. BCR-induced CD22 phosphorylation and Src homology 2 domain-containing protein tyrosine phosphatase-1/CD22 associations were also reduced, suggesting abrogation of negative regulatory signaling. By contrast, CD19/CD21 ligation using higher concentrations of SA-C3dg significantly inhibited BCR-induced [Ca2+]i responses and inhibited CD19, Lyn, CD22, and Syk phosphorylation. Therefore, C3d may enhance or inhibit Ag-specific humoral immune responses through both CD21-dependent and -independent mechanisms depending on the concentration and nature of the Ag-C3d complexes.

Authors
Lee, Y; Haas, KM; Gor, DO; Ding, X; Karp, DR; Greenspan, NS; Poe, JC; Tedder, TF
MLA Citation
Lee, Y, Haas, KM, Gor, DO, Ding, X, Karp, DR, Greenspan, NS, Poe, JC, and Tedder, TF. "Complement component C3d-antigen complexes can either augment or inhibit B lymphocyte activation and humoral immunity in mice depending on the degree of CD21/CD19 complex engagement." J Immunol 175.12 (December 15, 2005): 8011-8023.
PMID
16339538
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
175
Issue
12
Publish Date
2005
Start Page
8011
End Page
8023

CD molecules 2005: human cell differentiation molecules.

The immune system works through leukocytes interacting with each other, with other cells, with tissue matrices, with infectious agents, and with other antigens. These interactions are mediated by cell-surface glycoproteins and glycolipids. Antibodies against these leukocyte molecules have provided powerful tools for analysis of their structure, function, and distribution. Antibodies have been used widely in hematology, immunology, and pathology, and in research, diagnosis, and therapy. The associated CD nomenclature is commonly used when referring to leukocyte surface molecules and antibodies against them. It provides an essential classification for diagnostic and therapeutic purposes. The most recent (8th) Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA), held in Adelaide, Australia, in December 2004, allocated 95 new CD designations and made radical changes to its aims and future operational strategy in order to maintain its relevance to modern human biology and clinical practice.

Authors
Zola, H; Swart, B; Nicholson, I; Aasted, B; Bensussan, A; Boumsell, L; Buckley, C; Clark, G; Drbal, K; Engel, P; Hart, D; Horejsí, V; Isacke, C; Macardle, P; Malavasi, F; Mason, D; Olive, D; Saalmueller, A; Schlossman, SF; Schwartz-Albiez, R; Simmons, P; Tedder, TF; Uguccioni, M; Warren, H
MLA Citation
Zola, H, Swart, B, Nicholson, I, Aasted, B, Bensussan, A, Boumsell, L, Buckley, C, Clark, G, Drbal, K, Engel, P, Hart, D, Horejsí, V, Isacke, C, Macardle, P, Malavasi, F, Mason, D, Olive, D, Saalmueller, A, Schlossman, SF, Schwartz-Albiez, R, Simmons, P, Tedder, TF, Uguccioni, M, and Warren, H. "CD molecules 2005: human cell differentiation molecules." Blood 106.9 (November 1, 2005): 3123-3126.
PMID
16020511
Source
pubmed
Published In
Blood
Volume
106
Issue
9
Publish Date
2005
Start Page
3123
End Page
3126
DOI
10.1182/blood-2005-03-1338

CD22: A multifunctional lectin that regulates B lymphocyte survival and signal transduction

Authors
Tedder, TF; Poe, JC; Haas, KM
MLA Citation
Tedder, TF, Poe, JC, and Haas, KM. "CD22: A multifunctional lectin that regulates B lymphocyte survival and signal transduction." November 2005.
Source
wos-lite
Published In
Glycobiology
Volume
15
Issue
11
Publish Date
2005
Start Page
1197
End Page
1197

Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease.

Immunotherapy with unconjugated CD20 monoclonal antibodies has proven effective for treating non-Hodgkin's lymphoma and autoimmune disease. CD20 immunotherapy depletes mature B cells but does not effectively deplete pre-B or immature B cells, some B cell subpopulations, antibody-producing cells, or their malignant counterparts. Because CD19 is expressed earlier during B cell development, a therapeutic strategy for the treatment of early lymphoblastic leukemias/lymphomas was developed by using CD19-specific monoclonal antibodies in a transgenic mouse expressing human CD19. Pre-B cells and their malignant counterparts were depleted as well as antibody- and autoantibody-producing cells. These results demonstrate clinical utility for the treatment of diverse B cell malignancies, autoimmune disease, and humoral transplant rejection.

Authors
Yazawa, N; Hamaguchi, Y; Poe, JC; Tedder, TF
MLA Citation
Yazawa, N, Hamaguchi, Y, Poe, JC, and Tedder, TF. "Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease." Proc Natl Acad Sci U S A 102.42 (October 18, 2005): 15178-15183.
PMID
16217038
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
102
Issue
42
Publish Date
2005
Start Page
15178
End Page
15183
DOI
10.1073/pnas.0505539102

Humoral autoimmunity in mice overexpressing B cell surface CD19: vital role for MHC class II.

B6 mice bearing a transgene (Tg) for human CD19 (hCD19) harbor increased numbers of splenic Ig-secreting cells (IgSC), increased serum levels of total Ig and autoantibodies, but decreased numbers of splenic B cells. To assess the influence of MHC class II (MHCII) to this phenotype, MHCII-deficient CD19-Tg mice were generated. Compared to MHCII-sufficient CD19-Tg mice, splenic IgSC numbers and serum Ig and autoantibody levels were markedly diminished, and the decrease in splenic B cell numbers was aggravated. Remarkably, genetic reconstitution of these MHCII-deficient mice with a human DQ8 Tg resulted in a hierarchical restorative pattern. Restoration of splenic B cell numbers was complete; restoration of numbers of splenic IgSC and of serum Ig levels was partial; and restoration of circulating autoantibody levels was virtually non-existent. Thus, MHCII expression has a profound effect on B cells which can be uncoupled from global Ig and autoantibody production in the hCD19-Tg model. This raises the possibility that MHCII affects B cells in a manner that, at least in part, is independent of helper T cell function.

Authors
Stohl, W; Xu, D; Kim, KS; Tedder, TF; Sato, S
MLA Citation
Stohl, W, Xu, D, Kim, KS, Tedder, TF, and Sato, S. "Humoral autoimmunity in mice overexpressing B cell surface CD19: vital role for MHC class II." Clin Immunol 116.3 (September 2005): 257-264.
PMID
15963762
Source
pubmed
Published In
Clinical Immunology
Volume
116
Issue
3
Publish Date
2005
Start Page
257
End Page
264
DOI
10.1016/j.clim.2005.04.003

B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae.

B-1a and B-1b lymphocytes were found to exhibit specialized roles in providing immunity to Streptococcus pneumoniae and differ dramatically in their developmental requirements. Transgenic mice overexpressing CD19 (hCD19Tg) generated B-1a cells and natural antibodies that provided protection during infection, while CD19-deficient (CD19(-/-)) mice lacked B-1a cells, lacked natural antibodies, and were more susceptible to infection. By contrast, pneumococcal polysaccharide (PPS) immunization protected CD19(-/-) mice during lethal challenge, whereas hCD19Tg mice remained unprotected. This resulted from differences in the B-1b subset: the key population found to produce protective PPS-specific antibody in both wild-type and CD19(-/-) mice. Thus, CD19(-/-) mice generated B-1b cells and protective adaptive PPS-specific antibody responses, whereas hCD19Tg mice lacked B-1b cells and adaptive PPS-specific antibody responses. This reciprocal contribution of B-1a and B-1b subsets to innate and acquired immunity reveals an unexpected division of labor within the B-1 compartment that is normally balanced by their coordinated development.

Authors
Haas, KM; Poe, JC; Steeber, DA; Tedder, TF
MLA Citation
Haas, KM, Poe, JC, Steeber, DA, and Tedder, TF. "B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae." Immunity 23.1 (July 2005): 7-18.
PMID
16039575
Source
pubmed
Published In
Immunity
Volume
23
Issue
1
Publish Date
2005
Start Page
7
End Page
18
DOI
10.1016/j.immuni.2005.04.011

The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice.

Although anti-CD20 immunotherapy effectively treats human lymphoma and autoimmune disease, the in vivo effect of immunotherapy on tissue B cells and their subsets is generally unknown. To address this, anti-mouse CD20 mAbs were used in a mouse model in which the extent and kinetics of tissue B cell depletion could be assessed in vivo. CD20 mAb treatment depleted most mature B cells within 2 days, with 95-98% of B cells in the bone marrow, blood, spleen, lymph nodes, and gut-associated lymphoid tissues depleted by day 7, including marginal zone and follicular B cells. The few spleen B cells remaining after CD20 mAb treatment included pre-B, immature, transitional, and some B1 B cells that expressed CD20 at low levels. By contrast, peritoneal cavity B cells expressed normal CD20 densities and were coated with CD20 mAb, but only 30-43% of B1 cells and 43-78% of B2 cells were depleted by day 7. Spleen B cells adoptively transferred into the peritoneal cavity were similarly resistant to mAb-induced depletion, while transferred B cells that had migrated to the spleen were depleted. However, peritoneal B1 and B2 cells were effectively depleted in mAb-treated wild-type and C3-deficient mice by thioglycolate-induced monocyte migration into this otherwise privileged niche. Inflammation-elicited effector cells did not promote peritoneal cavity B cell depletion in FcR-deficient mice treated with CD20 mAb. Thus, the majority of CD20(+) cells and B cell subsets within lymphoid tissues and the peritoneum could be depleted efficiently in vivo through Fc-dependent, but C-independent pathways during anti-CD20 immunotherapy.

Authors
Hamaguchi, Y; Uchida, J; Cain, DW; Venturi, GM; Poe, JC; Haas, KM; Tedder, TF
MLA Citation
Hamaguchi, Y, Uchida, J, Cain, DW, Venturi, GM, Poe, JC, Haas, KM, and Tedder, TF. "The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice." Journal of immunology (Baltimore, Md. : 1950) 174.7 (April 2005): 4389-4399.
PMID
15778404
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
174
Issue
7
Publish Date
2005
Start Page
4389
End Page
4399
DOI
10.4049/jimmunol.174.7.4389

A new twist to the leukocyte adhesion cascade: intimate cooperation is key.

Leukocyte migration from blood into lymphoid and non-lymphoid tissues requires a highly orchestrated series of adhesive and signaling events. A network of adhesion molecules with overlapping functions mediate the capture, rolling and firm adhesion of leukocytes to the vascular endothelium. A new study adds a novel twist to this paradigm by demonstrating that two adhesion molecules, CD44 and VLA-4, must be physically associated with each other on activated T cells to mediate efficient rolling and firm adhesion.

Authors
Steeber, DA; Venturi, GM; Tedder, TF
MLA Citation
Steeber, DA, Venturi, GM, and Tedder, TF. "A new twist to the leukocyte adhesion cascade: intimate cooperation is key." Trends Immunol 26.1 (January 2005): 9-12. (Review)
PMID
15629403
Source
pubmed
Published In
Trends in Immunology
Volume
26
Issue
1
Publish Date
2005
Start Page
9
End Page
12
DOI
10.1016/j.it.2004.11.012

Role of the CD19 and CD21/35 receptor complex in innate immunity, host defense and autoimmunity.

Authors
Haas, KM; Tedder, TF
MLA Citation
Haas, KM, and Tedder, TF. "Role of the CD19 and CD21/35 receptor complex in innate immunity, host defense and autoimmunity." Adv Exp Med Biol 560 (2005): 125-139. (Review)
PMID
15934172
Source
pubmed
Published In
Advances in experimental medicine and biology
Volume
560
Publish Date
2005
Start Page
125
End Page
139
DOI
10.1007/0-387-24180-9_16

The CD19-CD21 signal transduction complex of B lymphocytes regulates the balance between health and autoimmune disease: systemic sclerosis as a model system.

Cell-surface CD19 functions as a general rheostat for defining intrinsic and antigen receptor-induced signaling thresholds critical for clonal expansion of the B cell pool and humoral immunity. CD19 also governs B cell responses initiated through the CD21 receptor, where complement C3d binding to CD21 links humoral immune responses with the innate immune system. Alterations in this signaling pathway can predispose mice and humans to autoantibody production and systemic autoimmunity. Transgenic mice that overexpress CD19 by 20-170% lose tolerance and generate autoantibodies. Likewise, B cells from CD21-deficient mice overexpress CD19 by approximately 50%, which leads to autoantibody production. Autoimmune patients with systemic sclerosis also overexpress CD19 by approximately 20%, which may contribute to their intrinsic B cell abnormalities and autoantibody production. Thus, chronic B cell activation resulting from augmented CD19 expression or signaling through the CD19 pathway may reveal a prototype autoimmune disease susceptibility pathway in mice and humans.

Authors
Tedder, TF; Poe, JC; Fujimoto, M; Haas, KM; Sato, S
MLA Citation
Tedder, TF, Poe, JC, Fujimoto, M, Haas, KM, and Sato, S. "The CD19-CD21 signal transduction complex of B lymphocytes regulates the balance between health and autoimmune disease: systemic sclerosis as a model system." Curr Dir Autoimmun 8 (2005): 55-90. (Review)
PMID
15564717
Source
pubmed
Published In
Current directions in autoimmunity
Volume
8
Publish Date
2005
Start Page
55
End Page
90
DOI
10.1159/000082087

CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction.

Recent advances in the study of CD22 indicate a complex role for this transmembrane glycoprotein member of the immunoglobulin superfamily in the regulation of B lymphocyte survival and proliferation. CD22 has been previously recognized as a potential lectin-like adhesion molecule that binds alpha2,6-linked sialic acid-bearing ligands and as an important regulator of B-cell antigen receptor (BCR) signaling. However, genetic studies in mice reveal that some CD22 functions are regulated by ligand binding, whereas other functions are ligand-independent and may only require expression of an intact CD22 cytoplasmic domain at the B-cell surface. Until recently, most of the functional activity of CD22 has been widely attributed to CD22's ability to recruit potent intracellular phosphatases and limit the intensity of BCR-generated signals. However, a more complex role for CD22 has recently emerged, including a central role in a novel regulatory loop controlling the CD19/CD21-Src-family protein tyrosine kinase (PTK) amplification pathway that regulates basal signaling thresholds and intensifies Src-family kinase activation after BCR ligation. CD22 is also central to the regulation of peripheral B-cell homeostasis and survival, the promotion of BCR-induced cell cycle progression, and is a potent regulator of CD40 signaling. Herein we discuss our current understanding of how CD22 governs these complex and overlapping processes, how alterations in these tightly controlled regulatory activities may influence autoimmune disease, and the current and future applications of CD22-directed therapies in oncology and autoimmunity.

Authors
Tedder, TF; Poe, JC; Haas, KM
MLA Citation
Tedder, TF, Poe, JC, and Haas, KM. "CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction." Adv Immunol 88 (2005): 1-50. (Review)
PMID
16227086
Source
pubmed
Published In
Advances in immunology
Volume
88
Publish Date
2005
Start Page
1
End Page
50
DOI
10.1016/S0065-2776(05)88001-0

Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs. SSc is associated with immune activation characterized by autoantibody production, lymphocyte activation, and release of various cytokines. The presence of autoantibodies is a central feature of immune activation in SSc. Although autoantibodies are thought to be closely linked to the pathogenesis of SSc, the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc, including skin fibrosis, remains unknown. Recent studies have revealed that B cells play a critical role in systemic autoimmunity and disease expression through various functions, including cytokine production in addition to autoantibody production. The B cell signaling thresholds are regulated by response regulators that augment or diminish B cell signals during responses to self and foreign antigens. Abnormal regulation of the response regulator function and expression may result in autoantibody production. Among these response regulators, CD19, which is a critical cell-surface signal transduction molecule of B cells, is the most potent positive regulator. Transgenic mice that overexpress CD19 by ∼3-fold lose tolerance and generate autoantibodies spontaneously. B cells from SSc patients exhibit a 20%-increase in CD19 expression that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by expanded naive B cells, activated but diminished memory B cells, and chronic hyper-reactivity of memory B cells, possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic hyper-reactivity. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling leads to skin fibrosis possibly through IL-6 overproduction, as well as autoantibody production, in tight-skin mice and SSc patients. © 2005 Elsevier Ltd. All rights reserved.

Authors
Sato, S; Fujimoto, M; Hasegawa, M; Takehara, K; Tedder, TF
MLA Citation
Sato, S, Fujimoto, M, Hasegawa, M, Takehara, K, and Tedder, TF. "Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis." Molecular Immunology 42.7 (2005): 821-831.
Source
scival
Published In
Molecular Immunology
Volume
42
Issue
7
Publish Date
2005
Start Page
821
End Page
831
DOI
10.1016/j.molimm.2005.01.009

Association of a functional CD19 polymorphism with susceptibility to systemic sclerosis.

OBJECTIVE: CD19 is overexpressed in B cells from patients with systemic sclerosis (SSc), and plays a crucial role not only for autoantibody production, but also for skin fibrosis in mouse models. We previously reported the association of a GT repeat polymorphism in the 3'-untranslated region (3'-UTR) of CD19 with human systemic lupus erythematosus. In this study, we examined whether CD19 polymorphisms are associated with genetic susceptibility to SSc. METHODS: A case-control association study was performed for CD19 polymorphisms, -499G>T in the promoter region and a GT repeat polymorphism in the 3'-UTR, in 134 patients with SSc and 96 healthy individuals recruited at Kanazawa University. CD19 expression levels in the peripheral blood naive and memory B cells from SSc patients were examined by 2-color flow cytometry. RESULTS: Carrier frequencies of the -499T allele in the promoter (odds ratio [OR] 2.18, 95% confidence interval [95% CI] 1.31-3.86, P = 0.003) and of the (GT)(14) allele in the 3'-UTR (OR 1.86, 95% CI 1.05-3.28, P = 0.03) were significantly increased in SSc patients compared with healthy controls. Association was particularly evident in patients with limited cutaneous SSc with anticentromere antibodies. These alleles were in linkage disequilibrium, but the -499T allele seemed to play a primary role. CD19 expression levels in peripheral blood B cells were significantly elevated in both naive (P = 0.0029) and memory (P = 0.0022) B cells from patients with SSc who had the -499T allele as compared with those without the -499T allele. CONCLUSION: The CD19 -499G>T polymorphism is associated with higher CD19 expression in B cells, and with susceptibility to SSc.

Authors
Tsuchiya, N; Kuroki, K; Fujimoto, M; Murakami, Y; Tedder, TF; Tokunaga, K; Takehara, K; Sato, S
MLA Citation
Tsuchiya, N, Kuroki, K, Fujimoto, M, Murakami, Y, Tedder, TF, Tokunaga, K, Takehara, K, and Sato, S. "Association of a functional CD19 polymorphism with susceptibility to systemic sclerosis." Arthritis Rheum 50.12 (December 2004): 4002-4007.
PMID
15593213
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
50
Issue
12
Publish Date
2004
Start Page
4002
End Page
4007
DOI
10.1002/art.20674

Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs. SSc is associated with immune activation characterized by autoantibody production, lymphocyte activation, and release of various cytokines. The presence of autoantibodies is a central feature of immune activation in SSc. Although autoantibodies are thought to be closely linked to the pathogenesis of SSc, the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc, including skin fibrosis, remains unknown. Recent studies have revealed that B cells play a critical role in systemic autoimmunity and disease expression through various functions, including cytokine production in addition to autoantibody production. The B cell signaling thresholds are regulated by response regulators that augment or diminish B cell signals during responses to self and foreign antigens. Abnormal regulation of the response regulator function and expression may result in autoantibody production. Among these response regulators, CD19, which is a critical cell-surface signal transduction molecule of B cells, is the most potent positive regulator. Transgenic mice that overexpress CD19 by approximately 3-fold lose tolerance and generate autoantibodies spontaneously. B cells from SSc patients exhibit a 20%-increase in CD19 expression that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by expanded naive B cells, activated but diminished memory B cells, and chronic hyper-reactivity of memory B cells, possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic hyper-reactivity. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling leads to skin fibrosis possibly through IL-6 overproduction, as well as autoantibody production, in tight-skin mice and SSc patients.

Authors
Sato, S; Fujimoto, M; Hasegawa, M; Takehara, K; Tedder, TF
MLA Citation
Sato, S, Fujimoto, M, Hasegawa, M, Takehara, K, and Tedder, TF. "Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis." Mol Immunol 41.12 (November 2004): 1123-1133. (Review)
PMID
15482848
Source
pubmed
Published In
Molecular Immunology
Volume
41
Issue
12
Publish Date
2004
Start Page
1123
End Page
1133
DOI
10.1016/j.molimm.2004.06.025

CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms.

The interaction of CD22 with alpha2,6-linked sialic acid ligands has been widely proposed to regulate B lymphocyte function and migration. Here, we generated gene-targeted mice that express mutant CD22 molecules that do not interact with these ligands. CD22 ligand binding regulated the expression of cell surface CD22, immunoglobulin M and major histocompatibility complex class II on mature B cells, maintenance of the marginal zone B cell population, optimal B cell antigen receptor-induced proliferation, and B cell turnover rates. However, CD22 negative regulation of calcium mobilization after B cell antigen receptor ligation, CD22 phosphorylation, recruitment of SHP-1 to CD22 and B cell migration did not require CD22 ligand engagement. These observations resolve longstanding questions regarding the physiological importance of CD22 ligand binding in the regulation of B cell function in vivo.

Authors
Poe, JC; Fujimoto, Y; Hasegawa, M; Haas, KM; Miller, AS; Sanford, IG; Bock, CB; Fujimoto, M; Tedder, TF
MLA Citation
Poe, JC, Fujimoto, Y, Hasegawa, M, Haas, KM, Miller, AS, Sanford, IG, Bock, CB, Fujimoto, M, and Tedder, TF. "CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms." Nat Immunol 5.10 (October 2004): 1078-1087.
PMID
15378059
Source
pubmed
Published In
Nature Immunology
Volume
5
Issue
10
Publish Date
2004
Start Page
1078
End Page
1087
DOI
10.1038/ni1121

B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse.

Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell signaling contribute to specific autoantibody production.

Authors
Asano, N; Fujimoto, M; Yazawa, N; Shirasawa, S; Hasegawa, M; Okochi, H; Tamaki, K; Tedder, TF; Sato, S
MLA Citation
Asano, N, Fujimoto, M, Yazawa, N, Shirasawa, S, Hasegawa, M, Okochi, H, Tamaki, K, Tedder, TF, and Sato, S. "B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse." Am J Pathol 165.2 (August 2004): 641-650.
PMID
15277237
Source
pubmed
Published In
The American journal of pathology
Volume
165
Issue
2
Publish Date
2004
Start Page
641
End Page
650
DOI
10.1016/S0002-9440(10)63328-7

The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy.

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell-, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti-mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcgammaRI- and FcgammaRIII-dependent pathways, whereas B cells were not eliminated in FcR common gamma chain-deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcgammaR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.

Authors
Uchida, J; Hamaguchi, Y; Oliver, JA; Ravetch, JV; Poe, JC; Haas, KM; Tedder, TF
MLA Citation
Uchida, J, Hamaguchi, Y, Oliver, JA, Ravetch, JV, Poe, JC, Haas, KM, and Tedder, TF. "The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy." J Exp Med 199.12 (June 21, 2004): 1659-1669.
PMID
15210744
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
199
Issue
12
Publish Date
2004
Start Page
1659
End Page
1669
DOI
10.1084/jem.20040119

Cutting edge: C3d functions as a molecular adjuvant in the absence of CD21/35 expression.

Complement component C3 covalently attaches to Ags following activation, where the C3d cleavage fragment can function as a molecular adjuvant to augment humoral immune responses. C3d is proposed to exert its adjuvant-like activities by targeting Ags to the C3d receptor (CD21/35) expressed by B cells and follicular dendritic cells. To directly assess the importance of CD21/35 in mediating the immunostimulatory effects of C3d, CD21/35-deficient (CD21/35(-/-)) mice were immunized with streptavidin (SA), SA-C3dg tetramers, recombinant HIV gp120 (gp120), or gp120 fused with linear multimers of C3d. Remarkably, SA- and gp120-specific Ab responses were significantly augmented in CD21/35(-/-) mice when these Ags were complexed with C3d in comparison to Ag alone. In fact, primary and secondary Ab responses and Ab-forming cell responses of CD21/35(-/-) mice approached those of wild-type mice immunized with SA-C3dg and gp120-C3d. Thus, C3d can function as a molecular adjuvant in the absence of CD21/35 expression.

Authors
Haas, KM; Toapanta, FR; Oliver, JA; Poe, JC; Weis, JH; Karp, DR; Bower, JF; Ross, TM; Tedder, TF
MLA Citation
Haas, KM, Toapanta, FR, Oliver, JA, Poe, JC, Weis, JH, Karp, DR, Bower, JF, Ross, TM, and Tedder, TF. "Cutting edge: C3d functions as a molecular adjuvant in the absence of CD21/35 expression." J Immunol 172.10 (May 15, 2004): 5833-5837.
PMID
15128761
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
172
Issue
10
Publish Date
2004
Start Page
5833
End Page
5837

Severely impaired B lymphocyte proliferation, survival, and induction of the c-Myc:Cullin 1 ubiquitin ligase pathway resulting from CD22 deficiency on the C57BL/6 genetic background.

Understanding the molecular mechanisms through which CD22 regulates B lymphocyte homeostasis, signal transduction, and tolerance is critical to defining normal B cell function and understanding the role of CD22 in autoimmunity. Therefore, CD22 function was examined in vivo and in vitro using B cells from CD22-deficient (CD22(-/-)) mice. Backcrossing of founder CD22(-/-) mice onto the C57BL/6 (B6) genetic background from a B6/129 mixed background resulted in a dramatically reduced B cell proliferative response following IgM ligation, characterized by a paucity of lymphoblasts and augmented apoptosis. Also, the phenotype of splenic B6 CD22(-/-) B cells was uniquely HSA(high) and IgD(low)/CD21(low) with intermediate levels of CD5 expression, although the percentages of mature and transitional B cells were normal. That B6 CD22(-/-) B cells predominantly underwent apoptosis following IgM ligation correlated with this unique tolerant phenotype, as well as defective induction of the c-Myc:Cullin 1 (CUL1) ubiquitin ligase pathway that is necessary for progression to the S phase of cell cycle. CD40 ligation compensated for CD22 deficiency by restoring lymphoblast development, proliferation, c-Myc and CUL1 expression, and protein ubiquitination/degradation in IgM-stimulated B6 CD22(-/-) B cell cultures. Thereby, this study expands our current understanding of the complex role of CD22 during B cell homeostasis and Ag responsiveness, and reveals that the impact of CD22 deficiency is dictated by the genetic background on which it is rendered. Moreover, this study defines CD22 and CD40 as the first examples of lymphocyte coreceptors that influence induction of the c-Myc:CUL1 ubiquitin ligase pathway.

Authors
Poe, JC; Haas, KM; Uchida, J; Lee, Y; Fujimoto, M; Tedder, TF
MLA Citation
Poe, JC, Haas, KM, Uchida, J, Lee, Y, Fujimoto, M, and Tedder, TF. "Severely impaired B lymphocyte proliferation, survival, and induction of the c-Myc:Cullin 1 ubiquitin ligase pathway resulting from CD22 deficiency on the C57BL/6 genetic background." J Immunol 172.4 (February 15, 2004): 2100-2110.
PMID
14764675
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
172
Issue
4
Publish Date
2004
Start Page
2100
End Page
2110

Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis.

Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4(+) T cells are selectively activated in the adventitia of affected arteries. In human GCA artery-severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83(+) dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia-media border. Adoptive T cell transfer into temporal artery-SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II-matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.

Authors
Ma-Krupa, W; Jeon, M-S; Spoerl, S; Tedder, TF; Goronzy, JJ; Weyand, CM
MLA Citation
Ma-Krupa, W, Jeon, M-S, Spoerl, S, Tedder, TF, Goronzy, JJ, and Weyand, CM. "Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis." J Exp Med 199.2 (January 19, 2004): 173-183.
PMID
14734523
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
199
Issue
2
Publish Date
2004
Start Page
173
End Page
183
DOI
10.1084/jem.20030850

Cerebroside sulfotransferase deficiency ameliorates L-selectin-dependent monocyte infiltration in the kidney after ureteral obstruction.

Mononuclear cells infiltrating the interstitium are involved in renal tubulointerstitial injury. The unilateral ureteral obstruction (UUO) is an established experimental model of renal interstitial inflammation. In our previous study, we postulated that L-selectin on monocytes is involved in their infiltration into the interstitium by UUO and that a sulfated glycolipid, sulfatide, is the physiological L-selectin ligand in the kidney. Here we tested the above hypothesis using sulfatide- and L-selectin-deficient mice. Sulfatide-deficient mice were generated by gene targeting of the cerebroside sulfotransferase (Cst) gene. Although the L-selectin-IgG chimera protein specifically bound to sulfatide fraction in acidic lipids from wild-type kidney, it did not show such binding in fractions of Cst(-/-) mice kidney, indicating that sulfatide is the major L-selectin-binding glycolipid in the kidney. The distribution of L-selectin ligand in wild-type mice changed after UUO; sulfatide was relocated from the distal tubules to the peritubular capillaries where monocytes infiltrate, suggesting that sulfatide relocated to the endothelium after UUO interacted with L-selectin on monocytes. In contrast, L-selectin ligand was not detected in Cst(-/-) mice irrespective of UUO treatment. Compared with wild-type mice, Cst(-/-) mice showed a considerable reduction in the number of monocytes/macrophages that infiltrated the interstitium after UUO. The number of monocytes/macrophages was also reduced to a similar extent in L-selectin(-/-) mice. Our results suggest that sulfatide is a major L-selectin-binding molecule in the kidney and that the interaction between L-selectin and sulfatide plays a critical role in monocyte infiltration into the kidney interstitium.

Authors
Ogawa, D; Shikata, K; Honke, K; Sato, S; Matsuda, M; Nagase, R; Tone, A; Okada, S; Usui, H; Wada, J; Miyasaka, M; Kawashima, H; Suzuki, Y; Suzuki, T; Taniguchi, N; Hirahara, Y; Tadano-Aritomi, K; Ishizuka, I; Tedder, TF; Makino, H
MLA Citation
Ogawa, D, Shikata, K, Honke, K, Sato, S, Matsuda, M, Nagase, R, Tone, A, Okada, S, Usui, H, Wada, J, Miyasaka, M, Kawashima, H, Suzuki, Y, Suzuki, T, Taniguchi, N, Hirahara, Y, Tadano-Aritomi, K, Ishizuka, I, Tedder, TF, and Makino, H. "Cerebroside sulfotransferase deficiency ameliorates L-selectin-dependent monocyte infiltration in the kidney after ureteral obstruction." J Biol Chem 279.3 (January 16, 2004): 2085-2090.
PMID
14583626
Source
pubmed
Published In
The Journal of biological chemistry
Volume
279
Issue
3
Publish Date
2004
Start Page
2085
End Page
2090
DOI
10.1074/jbc.M305809200

Mouse CD20 expression and function.

CD20 plays a role in human B cell proliferation and is an effective target for immunotherapy. In this study, mouse CD20 expression and biochemistry were assessed for the first time using a new panel of CD20-specific mAb, with CD20 function assessed using CD20-deficient (CD20(-/-)) mice. CD20 expression was B cell restricted and was initiated during late pre-B cell development. The frequency and density of CD20 expression increased during B cell maturation in the bone marrow, with a subpopulation of transitional IgM(hi) B cells expressing higher CD20 levels than the majority of mature recirculating B cells. Transitional T1 B cells in the spleen also expressed high CD20 levels, providing a useful new marker for this B cell subset. In CD20(-/-) mice, immature and mature B cell IgM expression was approximately 20-30% lower relative to B cells from wild-type littermates. In addition, CD19-induced intracellular calcium responses were significantly reduced in CD20(-/-) B cells, with a less dramatic effect on IgM-induced responses. These results reveal a role for CD20 in transmembrane Ca(2+) movement in mouse primary B cells that complements previous results obtained using human CD20 cDNA-transfected cell lines. Otherwise, B cell development, tissue localization, signal transduction, proliferation, T cell-dependent antibody responses and affinity maturation were normal in CD20(-/-) mice. Thus, mouse and human CD20 share similar patterns of expression and function. These studies thereby provide an animal model for studying CD20 function in vivo and the molecular mechanisms that influence anti-CD20 immunotherapy.

Authors
Uchida, J; Lee, Y; Hasegawa, M; Liang, Y; Bradney, A; Oliver, JA; Bowen, K; Steeber, DA; Haas, KM; Poe, JC; Tedder, TF
MLA Citation
Uchida, J, Lee, Y, Hasegawa, M, Liang, Y, Bradney, A, Oliver, JA, Bowen, K, Steeber, DA, Haas, KM, Poe, JC, and Tedder, TF. "Mouse CD20 expression and function." Int Immunol 16.1 (January 2004): 119-129.
PMID
14688067
Source
pubmed
Published In
International Immunology
Volume
16
Issue
1
Publish Date
2004
Start Page
119
End Page
129

In memoriam. D. Bernard Amos April 16, 1923-May 15, 2003.

Authors
Tedder, TF; Dawson, JR
MLA Citation
Tedder, TF, and Dawson, JR. "In memoriam. D. Bernard Amos April 16, 1923-May 15, 2003." J Immunol 171.12 (December 15, 2003): 6316-6317.
PMID
14662825
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
171
Issue
12
Publish Date
2003
Start Page
6316
End Page
6317

D. Bernard Amos April 16, 1923-May 15, 2003 - In memoriam

Authors
Tedder, TF; Dawson, JR
MLA Citation
Tedder, TF, and Dawson, JR. "D. Bernard Amos April 16, 1923-May 15, 2003 - In memoriam." JOURNAL OF IMMUNOLOGY 171.12 (December 15, 2003): 6316-6317.
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
171
Issue
12
Publish Date
2003
Start Page
6316
End Page
6317

L-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes.

L-selectin mediates rolling of lymphocytes in high endothelial venules (HEVs) of peripheral lymph nodes (PLNs). Cross-linking of L-selectin causes proteolytic shedding of its ectodomain, the physiological significance of which is unknown. To determine whether L-selectin shedding regulates lymphocyte migration, a mutant form that resists shedding (LdDeltaP-selectin) was engineered. Transgenic mice expressing either LDeltaP or wild-type (WT) L-selectin on T cells were crossed with L-selectin knockout (KO) mice. The cellularity and subset composition of secondary lymphoid organs did not differ between LDeltaP and WT mice, however, they were different from C57BL/6. Plasma levels of soluble L-selectin in LDeltaP mice were reduced to <5% of WT and C57BL/6 mice. The rolling properties of T lymphocytes from LDeltaP and WT mice on immobilized L-selectin ligands were similar. Furthermore, similar numbers of LDeltaP and WT T lymphocytes were recruited from the bloodstream into PLNs in mice, although LDeltaP T cells transmigrated HEVs more slowly. WT, but not LDeltaP-selectin, underwent rapid, metalloproteinase-dependent shedding after TCR engagement, and LDeltaP T cells retained the capacity to enter PLNs from the bloodstream. These results suggest that the ability to shed L-selectin is not required for T cell recirculation and homing to PLNs. However, L-selectin shedding from antigen-activated T cells prevents reentry into PLNs.

Authors
Galkina, E; Tanousis, K; Preece, G; Tolaini, M; Kioussis, D; Florey, O; Haskard, DO; Tedder, TF; Ager, A
MLA Citation
Galkina, E, Tanousis, K, Preece, G, Tolaini, M, Kioussis, D, Florey, O, Haskard, DO, Tedder, TF, and Ager, A. "L-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes." J Exp Med 198.9 (November 3, 2003): 1323-1335.
PMID
14597735
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
198
Issue
9
Publish Date
2003
Start Page
1323
End Page
1335
DOI
10.1084/jem.20030485

Leukocyte migration is regulated by L-selectin endoproteolytic release.

L-selectin mediates lymphocyte migration to peripheral lymph nodes and leukocyte rolling on vascular endothelium during inflammation. One unique feature that distinguishes L-selectin from other adhesion molecules is that it is rapidly cleaved from the cell surface after cellular activation. The biological significance of L-selectin endoproteolytic release was determined by generating gene-targeted mice expressing a modified receptor that was not cleaved from the cell surface. Blocking L-selectin cleavage on antigen-stimulated lymphocytes allowed their continued migration to peripheral lymph nodes and inhibited their short-term redirection to the spleen. Blocking homeostatic L-selectin cleavage also resulted in a constitutive 2-fold increase in overall L-selectin expression by leukocytes. As a result, neutrophils entered the inflamed peritoneum in greater numbers or for a longer duration. Thus, endoproteolytic cleavage regulates both homeostatic and activation-induced changes in cell surface L-selectin density, which directs the migration patterns of activated lymphocytes and neutrophils in vivo.

Authors
Venturi, GM; Tu, L; Kadono, T; Khan, AI; Fujimoto, Y; Oshel, P; Bock, CB; Miller, AS; Albrecht, RM; Kubes, P; Steeber, DA; Tedder, TF
MLA Citation
Venturi, GM, Tu, L, Kadono, T, Khan, AI, Fujimoto, Y, Oshel, P, Bock, CB, Miller, AS, Albrecht, RM, Kubes, P, Steeber, DA, and Tedder, TF. "Leukocyte migration is regulated by L-selectin endoproteolytic release." Immunity 19.5 (November 2003): 713-724.
PMID
14614858
Source
pubmed
Published In
Immunity
Volume
19
Issue
5
Publish Date
2003
Start Page
713
End Page
724

The tetraspanin CD81 regulates the expression of CD19 during B cell development in a postendoplasmic reticulum compartment.

CD81 is a widely expressed tetraspanin that associates in B cells with CD19 in the CD19-CD21-CD81 signaling complex. CD81 is necessary for normal CD19 expression; cd81(-/-) B cells express lower levels of CD19, especially cd81(-/-) small pre-BII cells, which are almost devoid of surface CD19. The dependence of CD19 expression on CD81 is specific to this particular tetraspanin since cd9(-/-) B cells express normal levels of CD19. Furthermore, expression of human CD81 in mouse cd81(-/-) B cells restored surface CD19 to normal levels. Quantitative analysis of CD19 mRNA demonstrated normal levels, even in cd81(-/-) pre-BII cells. Analysis of CD19 at the protein level identified two CD19 glycoforms in both wild-type and cd81(-/-) B cells. The higher M(r) glycoform is significantly reduced in cd81(-/-) B cells and is endoglycosidase H (endo-H) resistant. In contrast, the low M(r) glycoform is comparably expressed in cd81(-/-) and in wild-type B cells and is endo-H sensitive. Because endo-H sensitivity is tightly correlated with endoplasmic reticulum localization, we suggest that the dependency of CD19 expression on CD81 occurs in a postendoplasmic reticulum compartment where CD81 is necessary for normal trafficking or for surface membrane stability of CD19.

Authors
Shoham, T; Rajapaksa, R; Boucheix, C; Rubinstein, E; Poe, JC; Tedder, TF; Levy, S
MLA Citation
Shoham, T, Rajapaksa, R, Boucheix, C, Rubinstein, E, Poe, JC, Tedder, TF, and Levy, S. "The tetraspanin CD81 regulates the expression of CD19 during B cell development in a postendoplasmic reticulum compartment." J Immunol 171.8 (October 15, 2003): 4062-4072.
PMID
14530327
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
171
Issue
8
Publish Date
2003
Start Page
4062
End Page
4072

Ultraviolet light exposure suppresses contact hypersensitivity by abrogating endothelial intercellular adhesion molecule-1 up-regulation at the elicitation site.

Hapten sensitization through UV-exposed skin induces systemic immune suppression, which is experimentally demonstrated by inhibition of contact hypersensitivity (CHS). Although this UV-induced effect has been shown to be mediated by inhibition of the afferent phase of the CHS, the UV effects on the efferent (elicitation) phase remain unknown. In this study, UV effects on endothelial ICAM-1 expression at elicitation sites were first examined. Mice were sensitized by hapten application onto UV-exposed back skin, and ears were challenged 5 days later. ICAM-1 up-regulation at nonirradiated elicitation sites following hapten challenge was eliminated by UV exposure on sensitization sites distant from elicitation sites. To assess whether loss of the ICAM-1 up-regulation at elicitation sites contributed to UV-induced immunosuppression, we examined CHS responses in UV-exposed ICAM-1-deficient (ICAM-1(-/-)) mice that genetically lacked the ICAM-1 up-regulation. ICAM-1(-/-) mice exhibited reduced CHS responses without UV exposure, but UV exposure did not further reduce CHS responses in ICAM-1(-/-) mice. Furthermore, ICAM-1 deficiency did not affect the afferent limb, because ICAM-1(-/-) mice had normal generation of hapten-specific suppressor and effector T cells. This UV-induced immunosuppression was associated with a lack of TNF-alpha production after Ag challenge at elicitation sites. Local TNF-alpha injection before elicitation abrogated the UV-induced CHS inhibition with increased endothelial ICAM-1 expression. TNF-alpha production at elicitation sites was down-regulated by IL-10, a possible mediator produced by hapten-specific suppressor T cells that are generated by UV exposure. These results indicate that UV exposure inhibits CHS by abrogating up-regulation of endothelial ICAM-1 expression after Ag challenge at elicitation sites.

Authors
Komura, K; Hasegawa, M; Hamaguchi, Y; Saito, E; Kaburagi, Y; Yanaba, K; Kawara, S; Takehara, K; Seki, M; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Komura, K, Hasegawa, M, Hamaguchi, Y, Saito, E, Kaburagi, Y, Yanaba, K, Kawara, S, Takehara, K, Seki, M, Steeber, DA, Tedder, TF, and Sato, S. "Ultraviolet light exposure suppresses contact hypersensitivity by abrogating endothelial intercellular adhesion molecule-1 up-regulation at the elicitation site." J Immunol 171.6 (September 15, 2003): 2855-2862.
PMID
12960307
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
171
Issue
6
Publish Date
2003
Start Page
2855
End Page
2862

CD19 regulates innate immunity by the toll-like receptor RP105 signaling in B lymphocytes.

Lipopolysaccharide (LPS) is a major gram-negative bacterial component that stimulates innate immune response and also induces B-lymphocyte activation. Recent studies have revealed that common molecular patterns of microorganisms such as LPS are recognized by toll-like receptors (TLRs). B cells have 2 known TLRs that mediate LPS signaling, TLR4 and RP105 (CD180). While TLR4 is expressed on immune cells of various types, RP105 is preferentially expressed on mature B cells. Here we demonstrate that CD19 plays a major role in regulating signal transduction through RP105. Anti-RP105 ligation induced normal proliferation of B cells from mice deficient for MyD88, an adaptor protein that mediates most TLR pathways. By contrast, the loss of CD19 resulted in modest B-cell proliferation against anti-RP105 stimulation as well as LPS stimulation. LPS induced tyrosine phosphorylation of CD19, which was RP105-dependent but TLR4-independent. CD19 formed a complex with Lyn and Vav following RP105 ligation, and CD19 expression was required for optimal Lyn activation and Vav phosphorylation. Consistently, B cells deficient for CD19 exhibited specific defect in the activation of c-Jun N-terminal kinases following RP105 ligation and LPS stimulation. In contrast, CD19 and phosphatidylinositol 3-kinase independently regulated intracellular calcium mobilization induced by anti-RP105 stimulation. Thus, signaling through the B-cell-specific LPS receptor RP105 is uniquely regulated by the B-cell-specific signaling component, Lyn/CD19/Vav complex.

Authors
Yazawa, N; Fujimoto, M; Sato, S; Miyake, K; Asano, N; Nagai, Y; Takeuchi, O; Takeda, K; Okochi, H; Akira, S; Tedder, TF; Tamaki, K
MLA Citation
Yazawa, N, Fujimoto, M, Sato, S, Miyake, K, Asano, N, Nagai, Y, Takeuchi, O, Takeda, K, Okochi, H, Akira, S, Tedder, TF, and Tamaki, K. "CD19 regulates innate immunity by the toll-like receptor RP105 signaling in B lymphocytes." Blood 102.4 (August 15, 2003): 1374-1380.
PMID
12714520
Source
pubmed
Published In
Blood
Volume
102
Issue
4
Publish Date
2003
Start Page
1374
End Page
1380
DOI
10.1182/blood-2002-11-3573

Anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma xenografts.

CD22 is a membrane glycophosphoprotein found on nearly all healthy B-lymphocytes and most B-cell lymphomas. Recent in vitro studies have identified several anti-CD22 monoclonal antibodies (mAbs) that block the interaction of CD22 with its ligand. One of these mAbs, HB22.7, has been shown to effectively induce apoptosis in several B-cell lymphoma cell lines. Lymphoma xenograft studies with Raji-xenograft mice were used to assess the toxicity and efficacy of HB22.7 alone and with combined modality immunotherapy (CMIT) with yttrium (90)Y-DOTA-peptide-Lym-1 radioimmunotherapy (RIT). The effect of the sequence of these agents on the combined treatment was assessed by administering HB22.7 24 hours before, simultaneously with, or 24 hours after RIT. Within the groups treated with RIT alone or with RIT and HB22.7 (CMIT), the reduction in tumor volume was the greatest when HB22.7 was administered simultaneously with and 24 hours after RIT, and in the RIT treatment groups, this translated into the greatest overall response and survival, respectively. Overall survival rates at the end of the 84-day CMIT trial were 67% and 50% in the groups treated with HB22.7 simultaneously and 24 hours after RIT, respectively. This compared favorably with the untreated and the RIT alone groups, which had survival rates of 38% and 43% at the end of the trial. Surprisingly, when compared with untreated controls and all other treatment groups, the greatest cure and overall survival rates were observed in the group treated with HB22.7 alone, with 47% cured and 76% surviving at the end of the 84-day trial. RIT clearance was not affected by treatment with HB22.7. When compared with RIT alone, there was no significant additional hematologic (white blood cell, red blood cell, or platelet count) toxicity when HB22.7 was added to RIT. Nonhematologic toxicity (assessed as change in body weight) was also unchanged when HB22.7 was added to RIT. Thus the anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of (90)Y-DOTA-peptide-Lym-1 in lymphoma xenografts without significant toxicity.

Authors
Tuscano, JM; O'Donnell, RT; Miers, LA; Kroger, LA; Kukis, DL; Lamborn, KR; Tedder, TF; DeNardo, GL
MLA Citation
Tuscano, JM, O'Donnell, RT, Miers, LA, Kroger, LA, Kukis, DL, Lamborn, KR, Tedder, TF, and DeNardo, GL. "Anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma xenografts." Blood 101.9 (May 1, 2003): 3641-3647.
PMID
12511412
Source
pubmed
Published In
Blood
Volume
101
Issue
9
Publish Date
2003
Start Page
3641
End Page
3647
DOI
10.1182/blood-2002-08-2629

Relative contributions of selectins and intercellular adhesion molecule-1 to tissue injury induced by immune complex deposition.

Immune complex-induced tissue injury is mediated by inflammatory cell infiltration that is highly regulated by multiple adhesion molecules. To assess the relative contribution of adhesion molecules, including selectins and ICAM-1, in this pathogenetic process, the cutaneous passive Arthus reaction was examined in mice lacking E-selectin, P-selectin, or both L-selectin and ICAM-1 with anti-P- or E-selectin mAbs. Edema and hemorrhage were significantly reduced in P-selectin(-/-) mice compared with wild-type mice while they were not inhibited in E-selectin(-/-) mice. Combined E- and P-selectin blockade resulted in more significant reduction relative to L-selectin/ICAM-1(-/-) as well as P-selectin(-/-) mice. Remarkably, both E- and P-selectin blockade in L-selectin/ICAM-1(-/-) mice completely abrogated edema and hemorrhage. The inhibited edema and hemorrhage paralleled reduced infiltration of neutrophils and mast cells that expressed significant levels of P-selectin glycoprotein ligand-1. Similarly reduced infiltration of neutrophils and mast cells was observed in the peritoneal Arthus reaction and was associated partly with the decreased production of tumor necrosis factor-alpha and interleukin-6. The results of this study indicate that both endothelial selectins contribute predominantly to the Arthus reaction by regulating mast cell and neutrophil infiltration and that the full development of the Arthus reaction is mediated cooperatively by all selectins and ICAM-1.

Authors
Yanaba, K; Kaburagi, Y; Takehara, K; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Yanaba, K, Kaburagi, Y, Takehara, K, Steeber, DA, Tedder, TF, and Sato, S. "Relative contributions of selectins and intercellular adhesion molecule-1 to tissue injury induced by immune complex deposition." Am J Pathol 162.5 (May 2003): 1463-1473.
PMID
12707029
Source
pubmed
Published In
The American journal of pathology
Volume
162
Issue
5
Publish Date
2003
Start Page
1463
End Page
1473
DOI
10.1016/S0002-9440(10)64279-4

L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity.

Repeated Ag exposure results in a shift in the time course of contact hypersensitivity (CH) from a typical delayed-type to an immediate-type response followed by a late phase reaction. Chronic CH responses are clinically relevant to human skin allergic diseases, such as atopic dermatitis, that are usually caused by repeated stimulation with environmental Ags. Chronic inflammatory responses result in part from infiltrating leukocytes. To determine the role of leukocyte adhesion molecules in chronic inflammation, chronic CH responses were assessed in mice lacking L-selectin, ICAM-1, or both adhesion molecules. Following repeated hapten sensitization for 24 days at 2-day intervals, wild-type littermates developed an immediate-type response at 30 min after elicitation, followed by a late phase reaction. By contrast, loss of ICAM-1, L-selectin, or both, eliminated the immediate-type response and inhibited the late phase reaction. Similar results were obtained when wild-type littermates repeatedly exposed to hapten for 22 days were treated with mAbs to L-selectin and/or ICAM-1 before the elicitation on day 24. The lack of an immediate-type response on day 24 paralleled a lack of mast cell accumulation after 30 min of elicitation and decreased serum IgE production. Repeated Ag exposure in wild-type littermates resulted in increased levels of serum L-selectin, a finding also observed in atopic dermatitis patients. The current study demonstrates that L-selectin and ICAM-1 cooperatively regulate the induction of the immediate-type response by mediating mast cell accumulation into inflammatory sites and suggests that L-selectin and ICAM-1 are potential therapeutic targets for regulating human allergic reactions.

Authors
Shimada, Y; Hasegawa, M; Kaburagi, Y; Hamaguchi, Y; Komura, K; Saito, E; Takehara, K; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Shimada, Y, Hasegawa, M, Kaburagi, Y, Hamaguchi, Y, Komura, K, Saito, E, Takehara, K, Steeber, DA, Tedder, TF, and Sato, S. "L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity." J Immunol 170.8 (April 15, 2003): 4325-4334.
PMID
12682269
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
170
Issue
8
Publish Date
2003
Start Page
4325
End Page
4334

B lymphocytes contribute to autoimmune disease pathogenesis: current trends and clinical implications.

Abnormal B lymphocytes influence the pathogenesis of many autoimmune diseases, in addition to serving as the origin of pathogenic autoantibodies. Although aberrant B cell function and autoimmunity have complex polygenic origins, recent studies in mouse models of autoimmune diseases have revealed overlapping defects in signal transduction pathways that alter B cell survival or activation, and lead to an autoimmune phenotype. Discovery of these important signaling pathways in mice has lead to an intense search for B cell abnormalities that correlate with autoimmune diseases in humans. This search has identified potential targets for therapeutic intervention that are the focus of planned and ongoing human clinical trials. This promises an arsenal of highly targeted, less toxic therapies focused on restoring normal B cell function that will eliminate pathogenic autoantibodies and replace the current use of immunosuppressive drugs.

Authors
Tuscano, JM; Harris, GS; Tedder, TF
MLA Citation
Tuscano, JM, Harris, GS, and Tedder, TF. "B lymphocytes contribute to autoimmune disease pathogenesis: current trends and clinical implications." Autoimmun Rev 2.2 (March 2003): 101-108. (Review)
PMID
12848966
Source
pubmed
Published In
Autoimmunity Reviews
Volume
2
Issue
2
Publish Date
2003
Start Page
101
End Page
108

Utraviolet light exposure suppresses contact hypersensitivity by abrogating endothelial intercellular adhesion molecule-1 up-regulation at the elicitation site

Hapten sensitization through UV-exposed skin induces systemic immune suppression, which is experimentally demonstrated by inhibition of contact hypersensitivity (CHS). Although this UV-induced effect has been shown to be mediated by inhibition of the afferent phase of the CHS, the UV effects on the efferent (elicitation) phase remain unknown. In this study, UV effects on endothelial ICAM-1 expression at elicitation sites were first examined. Mice were sensitized by hapten application onto UV-exposed back skin, and ears were challenged 5 days later. ICAM-1 up-regulation at nonirradiated elicitation sites following hapten challenge was eliminated by UV exposure on sensitization sites distant from elicitation sites. To assess whether loss of the ICAM-1 up-regulation at elicitation sites contributed to UV-induced immunosuppression, we examined CHS responses in UV-exposed ICAM-1-deficient (ICAM-1-/-) mice that genetically lacked the ICAM-1 up-regulation. ICAM-1-/- mice exhibited reduced CHS responses without UV exposure, but UV exposure did not further reduce CHS responses in ICAM-1-/- mice. Furthermore, ICAM-1 deficiency did not affect the afferent limb, because ICAM-1 -/- mice had normal generation of hapten-specific suppressor and effector T cells. This UV-induced immunosuppression was associated with a lack of TNF-α production after Ag challenge at elicitation sites. Local TNF-α injection before elicitation abrogated the UV-induced CHS inhibition with increased endothelial ICAM-1 expression. TNF-α production at elicitation sites was down-regulated by IL-10, a possible mediator produced by hapten-specific suppressor T cells that are generated by UV exposure. These results indicate that UV exposure inhibits CHS by abrogating up-regulation of endothelial ICAM-1 expression after Ag challenge at elicitation sites.

Authors
Komura, K; Hasegawa, M; Hamaguchi, Y; Saito, E; Kaburagi, Y; Yanaba, K; Kawara, S; Takehara, K; Seki, M; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Komura, K, Hasegawa, M, Hamaguchi, Y, Saito, E, Kaburagi, Y, Yanaba, K, Kawara, S, Takehara, K, Seki, M, Steeber, DA, Tedder, TF, and Sato, S. "Utraviolet light exposure suppresses contact hypersensitivity by abrogating endothelial intercellular adhesion molecule-1 up-regulation at the elicitation site." Journal of Immunology 171.6 (2003): 2855-2862.
Source
scival
Published In
Journal of Immunology
Volume
171
Issue
6
Publish Date
2003
Start Page
2855
End Page
2862

Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses.

The CD21/35 receptor provides an important link between innate and adaptive immunity. Its importance during protective immune responses to encapsulated extracellular bacteria was assessed using a new line of mice completely deficient in CD21/35 expression (CD21/35(-/-)). CD21/35 expression was essential for the rapid trapping of C3dg-antigen complexes by B cells in vivo, especially in splenic marginal zones. Despite normal B cell development in CD21/35(-/-) mice, T cell-independent and -dependent antibody responses to low-dose antigens were significantly decreased, with a striking impairment in IgG3 responses. Accordingly, CD21/35(-/-) mice were more susceptible to acute lethal Streptococcus pneumoniae infection. Thus, CD21/35 expression is critical for early protective antibody responses to lethal pathogens that rapidly multiply and quickly overwhelm the immune system.

Authors
Haas, KM; Hasegawa, M; Steeber, DA; Poe, JC; Zabel, MD; Bock, CB; Karp, DR; Briles, DE; Weis, JH; Tedder, TF
MLA Citation
Haas, KM, Hasegawa, M, Steeber, DA, Poe, JC, Zabel, MD, Bock, CB, Karp, DR, Briles, DE, Weis, JH, and Tedder, TF. "Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses." Immunity 17.6 (December 2002): 713-723.
PMID
12479818
Source
pubmed
Published In
Immunity
Volume
17
Issue
6
Publish Date
2002
Start Page
713
End Page
723

Intercellular adhesion molecule-1 and L-selectin regulate bleomycin-induced lung fibrosis.

The development of bleomycin-induced lung injury, a model of pulmonary fibrosis, results from inflammatory cell infiltration, a process highly regulated by the expression of multiple adhesion molecules. At present, the identity and role of the adhesion molecules involved in the fibrotic process are unknown. Therefore, bleomycin-induced pulmonary fibrosis was examined in mice lacking L-selectin (L-selectin(-/-)) expression, intercellular adhesion molecule-1 (ICAM-1) expression, or both. After 16 days of intratracheal bleomycin challenge, collagen deposition was inhibited in both L-selectin(-/-) and ICAM-1(-/-) mice when compared with wild-type littermates. Interestingly, collagen deposition was virtually eliminated in L-selectin/ICAM-1(-/-) mice relative to either the L-selectin(-/-) or ICAM-1(-/-) mice. Decreased pulmonary fibrosis was associated with reduced accumulation of leukocytes, including neutrophils and lymphocytes. Decreased mRNA expression of proinflammatory cytokines and transforming growth factor (TGF)-beta1 paralleled the inhibition of collagen deposition. The present study indicates that L-selectin and ICAM-1 play a critical role in pulmonary fibrosis by mediating the accumulation of leukocytes, which regulate the production of proinflammatory cytokines and TGF-beta1. This suggests that these adhesion molecules are potential therapeutic targets for inhibiting human pulmonary fibrosis.

Authors
Hamaguchi, Y; Nishizawa, Y; Yasui, M; Hasegawa, M; Kaburagi, Y; Komura, K; Nagaoka, T; Saito, E; Shimada, Y; Takehara, K; Kadono, T; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Hamaguchi, Y, Nishizawa, Y, Yasui, M, Hasegawa, M, Kaburagi, Y, Komura, K, Nagaoka, T, Saito, E, Shimada, Y, Takehara, K, Kadono, T, Steeber, DA, Tedder, TF, and Sato, S. "Intercellular adhesion molecule-1 and L-selectin regulate bleomycin-induced lung fibrosis." Am J Pathol 161.5 (November 2002): 1607-1618.
PMID
12414509
Source
pubmed
Published In
The American journal of pathology
Volume
161
Issue
5
Publish Date
2002
Start Page
1607
End Page
1618
DOI
10.1016/S0002-9440(10)64439-2

Leukocyte rolling velocities and migration are optimized by cooperative L-selectin and intercellular adhesion molecule-1 functions.

Selectin family members largely mediate initial tethering and rolling of leukocytes on vascular endothelium, whereas integrin and Ig family members are essential for leukocyte firm adhesion. To quantify functional synergy between L-selectin and Ig family members during leukocyte rolling, the EA.hy926 human vascular endothelial line was transfected with either fucosyltransferase VII (926-FtVII) cDNA to generate L-selectin ligands alone or together with ICAM-1 cDNA (926-FtVII/ICAM-1). The ability of transfected 926 cells to support human leukocyte interactions was assessed in vitro using parallel plate flow chamber assays. Lymphocyte rolling on 926-FtVII cells was increased by approximately 70% when ICAM-1 was expressed at physiological levels. Although initial tether formation was similar for both cell types, lymphocyte rolling was 26% slower on 926-FtVII/ICAM-1 cells. Pretreatment of lymphocytes with an anti-CD18 mAb eliminated the increase in rolling, and all rolling was blocked by anti-L-selectin mAb. In addition, rolling velocities of lymphocytes from CD18-hypomorphic mice were 48% faster on 926-FtVII/ICAM-1 cells, with a similar reduction in rolling frequency relative to wild-type lymphocytes. CD18-hypomorphic lymphocytes also showed an approximately 40% decrease in migration to peripheral and mesenteric lymph nodes during in vivo migration assays compared with wild-type lymphocytes. Likewise, wild-type lymphocyte migration to peripheral lymph nodes was reduced by approximately 50% in ICAM-1(-/-) recipient mice. Similar to human lymphocytes, human neutrophils showed enhanced rolling interactions on 926-FtVII/ICAM-1 cells, but also firmly adhered. Thus, in addition to mediating leukocyte firm adhesion, CD18 integrin/ICAM-1 interactions regulate leukocyte rolling velocities and thereby optimize L-selectin-mediated leukocyte rolling.

Authors
Kadono, T; Venturi, GM; Steeber, DA; Tedder, TF
MLA Citation
Kadono, T, Venturi, GM, Steeber, DA, and Tedder, TF. "Leukocyte rolling velocities and migration are optimized by cooperative L-selectin and intercellular adhesion molecule-1 functions." J Immunol 169.8 (October 15, 2002): 4542-4550.
PMID
12370391
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
169
Issue
8
Publish Date
2002
Start Page
4542
End Page
4550

A functional role for circulating mouse L-selectin in regulating leukocyte/endothelial cell interactions in vivo.

L-selectin mediates the initial capture and subsequent rolling of leukocytes along inflamed vascular endothelium and mediates lymphocyte migration to peripheral lymphoid tissues. Leukocyte activation induces rapid endoproteolytic cleavage of L-selectin from the cell surface, generating soluble L-selectin (sL-selectin). Because human sL-selectin retains ligand-binding activity in vitro, mouse sL-selectin and its in vivo relevance were characterized. Comparable with humans, sL-selectin was present in adult C57BL/6 mouse sera at approximately 1.7 micro g/ml. Similar levels of sL-selectin were present in sera from multiple mouse strains, despite their pronounced differences in cell surface L-selectin expression levels. Adhesion molecule-deficient mice prone to spontaneous chronic inflammation and mice suffering from leukemia/lymphoma had 2.5- and 20-fold increased serum sL-selectin levels, respectively. By contrast, serum sL-selectin levels were reduced by 70% in Rag-deficient mice lacking mature lymphocytes. The majority of serum sL-selectin had a molecular mass of 65-75 kDa, consistent with its lymphocyte origin. Slow turnover may explain the relatively high levels of sL-selectin in vivo. The t(1/2) of sL-selectin, assessed by transferring sera from wild-type mice into L-selectin-deficient mice and monitoring serum sL-selectin levels by ELISA, was >20 h, and it remained detectable for longer than 1 wk. Short-term in vivo lymphocyte migration assays demonstrated that near physiologic levels ( approximately 0.9 micro g/ml) of sL-selectin decreased lymphocyte migration to peripheral lymph nodes by >30%, with dose-dependent inhibition occurring with increasing sL-selectin concentrations. These results suggest that sL-selectin influences lymphocyte migration in vivo and that the increased sL-selectin levels present in certain pathologic conditions may adversely affect leukocyte migration.

Authors
Tu, L; Poe, JC; Kadono, T; Venturi, GM; Bullard, DC; Tedder, TF; Steeber, DA
MLA Citation
Tu, L, Poe, JC, Kadono, T, Venturi, GM, Bullard, DC, Tedder, TF, and Steeber, DA. "A functional role for circulating mouse L-selectin in regulating leukocyte/endothelial cell interactions in vivo." J Immunol 169.4 (August 15, 2002): 2034-2043.
PMID
12165530
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
169
Issue
4
Publish Date
2002
Start Page
2034
End Page
2043

CD19-CD21 complex regulates an intrinsic Src family kinase amplification loop that links innate immunity with B-lymphocyte intracellular calcium responses.

CD19 is a B-lymphocyte cell surface molecule that functions as a general response regulator or rheostat, which defines intrinsic and B-cell antigen receptor-induced signalling thresholds that are critical for humoral immunity and expansion of the peripheral B-cell pool. In addition, B-cell responses are influenced by signals transduced through a CD19-CD21 cell surface receptor complex, where the binding of complement C3d to CD21 links humoral immune responses with the innate immune system. This review outlines recent biochemical and genetic studies that characterize the signal transduction pathways utilized by this receptor complex to regulate B-cell intracellular calcium responses.

Authors
Tedder, TF; Haas, KM; Poe, JC
MLA Citation
Tedder, TF, Haas, KM, and Poe, JC. "CD19-CD21 complex regulates an intrinsic Src family kinase amplification loop that links innate immunity with B-lymphocyte intracellular calcium responses." Biochem Soc Trans 30.4 (August 2002): 807-811. (Review)
PMID
12196203
Source
pubmed
Published In
Biochemical Society transactions
Volume
30
Issue
4
Publish Date
2002
Start Page
807
End Page
811

L-selectin dimerization enhances tether formation to properly spaced ligand.

Selectin counterreceptors are glycoprotein scaffolds bearing multiple carbohydrate ligands with exceptional ability to tether flowing cells under disruptive shear forces. Bond clusters may facilitate formation and stabilization of selectin tethers. L-selectin ligation has been shown to enhance L-selectin rolling on endothelial surfaces. We now report that monoclonal antibodies-induced L-selectin dimerization enhances L-selectin leukocyte tethering to purified physiological L-selectin ligands and glycopeptides. Microkinetic analysis of individual tethers suggests that leukocyte rolling is enhanced through the dimerization-induced increase in tether formation, rather than by tether stabilization. Notably, L-selectin dimerization failed to augment L-selectin-mediated adhesion below a threshold ligand density, suggesting that L-selectin dimerization enhanced adhesiveness only to properly clustered ligand. In contrast, an epidermal growth factor domain substitution of L-selectin enhanced tether formation to L-selectin ligands irrespective of ligand density, suggesting that this domain controls intrinsic ligand binding properties of L-selectin without inducing L-selectin dimerization. Strikingly, at low ligand densities, where L-selectin tethering was not responsive to dimerization, elevated shear stress restored sensitivity of tethering to selectin dimerization. This is the first indication that shear stress augments effective selectin ligand density at local contact sites by promoting L-selectin encounter of immobilized ligand.

Authors
Dwir, O; Steeber, DA; Schwarz, US; Camphausen, RT; Kansas, GS; Tedder, TF; Alon, R
MLA Citation
Dwir, O, Steeber, DA, Schwarz, US, Camphausen, RT, Kansas, GS, Tedder, TF, and Alon, R. "L-selectin dimerization enhances tether formation to properly spaced ligand." J Biol Chem 277.24 (June 14, 2002): 21130-21139.
PMID
11907045
Source
pubmed
Published In
The Journal of biological chemistry
Volume
277
Issue
24
Publish Date
2002
Start Page
21130
End Page
21139
DOI
10.1074/jbc.M201999200

Complementary roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction.

CD19 and Bruton's tyrosine kinase (Btk) may function along common signaling pathways in regulating intrinsic and B cell Ag receptor (BCR)-induced signals. To identify physical and functional interactions between CD19 and Btk, a CD19-negative variant of the A20 B cell line was isolated, and CD19-deficient (CD19(-/-)) and CD19-overexpressing mice with the X-linked immunodeficient (Xid; Btk) mutation were generated. In A20 cells, Btk physically associated with CD19 following BCR engagement. CD19 and Btk interactions were not required for initial Btk phosphorylation, but CD19 expression maintained Btk in an activated state following BCR engagement. In primary B cells, CD19 signaling also required downstream Btk function since CD19-induced intracellular Ca(2+) ([Ca(2+)](i)) responses were modest in Xid B cells. In addition, CD19 overexpression did not normalize the Xid phenotype and most phenotypic and functional hallmarks of CD19 overexpression were not evident in these mice. However, CD19 and Btk also regulate independent signaling pathways since their combined loss had additive inhibitory effects on BCR-induced [Ca(2+)](i) responses and CD19 deficiency induced a severe immunodeficiency in Xid mice. Thus, CD19 expression amplifies or prolongs Btk-mediated signaling, rather than serving as a required agent for Btk activation. Consistent with this, phosphatidylinositol 3-monophosphate kinase and Akt activation were normal in CD19(-/-) B cells following IgM engagement, although their kinetics of activation was altered. Thus, these biochemical and compound gene dosage studies indicate that Btk activation and [Ca(2+)](i) responses following BCR engagement are regulated through multiple pathways, including a CD19/Src family kinase-dependent pathway that promotes the longevity of Btk signaling.

Authors
Fujimoto, M; Poe, JC; Satterthwaite, AB; Wahl, MI; Witte, ON; Tedder, TF
MLA Citation
Fujimoto, M, Poe, JC, Satterthwaite, AB, Wahl, MI, Witte, ON, and Tedder, TF. "Complementary roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction." J Immunol 168.11 (June 1, 2002): 5465-5476.
PMID
12023340
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
168
Issue
11
Publish Date
2002
Start Page
5465
End Page
5476

CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse.

The tight-skin (TSK/+) mouse, a genetic model for human systemic sclerosis (SSc), develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. Although molecular mechanisms explaining the development of fibrosis and autoimmunity in SSc patients or TSK/+ mice remain unknown, we recently demonstrated that SSc patients overexpress CD19, an important regulatory molecule expressed by B lymphocytes. B cells from CD19-deficient mice are hyporesponsive to transmembrane signals, while B cells overexpressing CD19 are hyperresponsive and generate autoantibodies. In this study, TSK/+ B cells also exhibited a hyperresponsive phenotype with decreased surface IgM expression, enhanced serum Ig production, and spontaneous autoantibody production. Moreover, CD19 tyrosine phosphorylation was constitutively augmented in TSK/+ B cells. CD19-mediated [Ca(2+)](i) responses, Vav phosphorylation, and Lyn kinase activity were similarly enhanced. Studies of TSK/+ mice deficient in CD19 expression demonstrated that CD19 deficiency significantly decreased skin fibrosis in TSK/+ mice. Additionally, CD19 loss in TSK/+ mice upregulated surface IgM expression and completely abrogated hyper-gamma-globulinemia and autoantibody production. CD19 deficiency also inhibited IL-6 production by TSK/+ B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling in TSK/+ mice leads to skin sclerosis possibly through IL-6 overproduction as well as autoimmunity.

Authors
Saito, E; Fujimoto, M; Hasegawa, M; Komura, K; Hamaguchi, Y; Kaburagi, Y; Nagaoka, T; Takehara, K; Tedder, TF; Sato, S
MLA Citation
Saito, E, Fujimoto, M, Hasegawa, M, Komura, K, Hamaguchi, Y, Kaburagi, Y, Nagaoka, T, Takehara, K, Tedder, TF, and Sato, S. "CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse." J Clin Invest 109.11 (June 2002): 1453-1462.
PMID
12045259
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
109
Issue
11
Publish Date
2002
Start Page
1453
End Page
1462
DOI
10.1172/JCI15078

CD83 expression influences CD4+ T cell development in the thymus.

T lymphocyte selection and lineage commitment in the thymus requires multiple signals. Herein, CD4+ T cell generation required engagement of CD83, a surface molecule expressed by thymic epithelial and dendritic cells. CD83-deficient (CD83-/-) mice had a specific block in CD4+ single-positive thymocyte development without increased CD4+CD8+ double- or CD8+ single-positive thymocytes. This resulted in a selective 75%-90% reduction in peripheral CD4+ T cells, predominantly within the naive subset. Wild-type thymocytes and bone marrow stem cells failed to differentiate into mature CD4+ T cells when transferred into CD83-/- mice, while CD83-/- thymocytes and stem cells developed normally in wild-type mice. Thereby, CD83 expression represents an additional regulatory component for CD4+ T cell development in the thymus.

Authors
Fujimoto, Y; Tu, L; Miller, AS; Bock, C; Fujimoto, M; Doyle, C; Steeber, DA; Tedder, TF
MLA Citation
Fujimoto, Y, Tu, L, Miller, AS, Bock, C, Fujimoto, M, Doyle, C, Steeber, DA, and Tedder, TF. "CD83 expression influences CD4+ T cell development in the thymus." Cell 108.6 (March 22, 2002): 755-767.
PMID
11955430
Source
pubmed
Published In
Cell
Volume
108
Issue
6
Publish Date
2002
Start Page
755
End Page
767

Intercellular adhesion molecule-1 and L-selectin regulate bleomycin-induced lung fibrosis and neutrophil immigration

Authors
Hamaguchi, Y; Takehara, K; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Hamaguchi, Y, Takehara, K, Steeber, DA, Tedder, TF, and Sato, S. "Intercellular adhesion molecule-1 and L-selectin regulate bleomycin-induced lung fibrosis and neutrophil immigration." FASEB JOURNAL 16.5 (March 22, 2002): A1053-A1054.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
16
Issue
5
Publish Date
2002
Start Page
A1053
End Page
A1054

Cutaneous reverse Arthus reaction requires expression of intercellular adhesion molecule-1 or L-selectin

Authors
Sato, S; Kaburagi, Y; Hasegawa, M; Nagaoka, T; Hamaguchi, Y; Kadono, T; Steeber, DA; Tedder, TF; Takehara, KT
MLA Citation
Sato, S, Kaburagi, Y, Hasegawa, M, Nagaoka, T, Hamaguchi, Y, Kadono, T, Steeber, DA, Tedder, TF, and Takehara, KT. "Cutaneous reverse Arthus reaction requires expression of intercellular adhesion molecule-1 or L-selectin." FASEB JOURNAL 16.5 (March 22, 2002): A1051-A1052.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
16
Issue
5
Publish Date
2002
Start Page
A1051
End Page
A1052

CD22 and CD40 cooperatively regulate B lymphocyte survival

Authors
Poe, JC; Inaoki, M; Haas, KM; Nagaoka, T; Uchida, J; Fujimoto, M; Tedder, TF
MLA Citation
Poe, JC, Inaoki, M, Haas, KM, Nagaoka, T, Uchida, J, Fujimoto, M, and Tedder, TF. "CD22 and CD40 cooperatively regulate B lymphocyte survival." FASEB JOURNAL 16.4 (March 20, 2002): A705-A705.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
16
Issue
4
Publish Date
2002
Start Page
A705
End Page
A705

CD19 amplification of B lymphocyte Ca2+ responses: A role for Lyn sequestration in extinguishing negative regulation

Authors
Fujimoto, M; Poe, JC; Hasegawa, M; Tedder, TF
MLA Citation
Fujimoto, M, Poe, JC, Hasegawa, M, and Tedder, TF. "CD19 amplification of B lymphocyte Ca2+ responses: A role for Lyn sequestration in extinguishing negative regulation." FASEB JOURNAL 16.4 (March 20, 2002): A703-A703.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
16
Issue
4
Publish Date
2002
Start Page
A703
End Page
A703

CD19 regulates signaling thresholds that contribute to autoimmunity and skin fibrosis in tight skin mice

Authors
Sato, S; Saito, E; Fujimoto, M; Hasegawa, M; Hamaguchi, A; Nagaoka, T; Tedder, TF; Takehara, K
MLA Citation
Sato, S, Saito, E, Fujimoto, M, Hasegawa, M, Hamaguchi, A, Nagaoka, T, Tedder, TF, and Takehara, K. "CD19 regulates signaling thresholds that contribute to autoimmunity and skin fibrosis in tight skin mice." FASEB JOURNAL 16.4 (March 20, 2002): A328-A328.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
16
Issue
4
Publish Date
2002
Start Page
A328
End Page
A328

L-selectin is not required for T cell-mediated autoimmune diabetes.

Administration of anti-L-selectin (CD62L) mAb to neonatal nonobese diabetic (NOD) mice mediates long term protection against the development of insulitis and overt diabetes. These results suggested that CD62L has a key role in the general function of beta cell-specific T cells. To further examine the role of CD62L in the development of type 1 diabetes, NOD mice lacking CD62L were established. The onset and frequency of overt diabetes were equivalent among CD62L(+/+), CD62L(+/-), and CD62L(-/-) NOD littermates. Furthermore, patterns of T cell activation, migration, and beta cell-specific reactivity were similar in NOD mice of all three genotypes. Adoptive transfer experiments with CD62L(-/-) CD4(+) T cells prepared from BDC2.5 TCR transgenic mice revealed no apparent defects in migration to pancreatic lymph nodes, proliferation in response to beta cell Ag, or induction of diabetes in NOD.scid recipients. In conclusion, CD62L expression is not essential for the development of type 1 diabetes in NOD mice.

Authors
Friedline, RH; Wong, CP; Steeber, DA; Tedder, TF; Tisch, R
MLA Citation
Friedline, RH, Wong, CP, Steeber, DA, Tedder, TF, and Tisch, R. "L-selectin is not required for T cell-mediated autoimmune diabetes." J Immunol 168.6 (March 15, 2002): 2659-2666.
PMID
11884430
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
168
Issue
6
Publish Date
2002
Start Page
2659
End Page
2666

The cutaneous reverse Arthus reaction requires intercellular adhesion molecule 1 and L-selectin expression.

The deposition of immune complexes (IC) induces an acute inflammatory response with tissue injury. IC-induced inflammation is mediated by inflammatory cell infiltration, a process highly regulated by expression of multiple adhesion molecules. To assess the role of L-selectin and ICAM-1 in this pathogenetic process, the cutaneous reverse passive Arthus reaction was examined in mice lacking L-selectin (L-selectin(-/-)), ICAM-1 (ICAM-1(-/-)), or both (L-selectin/ICAM-1(-/-)). Edema and hemorrhage, which peaked 4 and 8 h after IC challenge, respectively, were significantly reduced in L-selectin(-/-), ICAM-1(-/-), and L-selectin/ICAM-1(-/-) mice compared with wild-type littermates. In general, edema and hemorrhage were more significantly inhibited in ICAM-1(-/-) mice than in L-selectin(-/-) mice, but were most significantly reduced in L-selectin/ICAM-1(-/-) mice compared with ICAM-1(-/-) or L-selectin(-/-) mice. Decreased edema and hemorrhage correlated with reduced neutrophil and mast cell infiltration in all adhesion molecule-deficient mice, but leukocyte infiltration was most affected in L-selectin/ICAM-1(-/-) mice. Reduced neutrophil and mast cell infiltration was also observed for all mutant mice in the peritoneal Arthus reaction. Furthermore, cutaneous TNF-alpha production was inhibited in each deficient mouse, which paralleled the reductions in cutaneous inflammation. These results indicate that ICAM-1 and L-selectin cooperatively contribute to the cutaneous Arthus reaction by regulating neutrophil and mast cell recruitment and suggest that ICAM-1 and L-selectin are therapeutic targets for human IC-mediated disease.

Authors
Kaburagi, Y; Hasegawa, M; Nagaoka, T; Shimada, Y; Hamaguchi, Y; Komura, K; Saito, E; Yanaba, K; Takehara, K; Kadono, T; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Kaburagi, Y, Hasegawa, M, Nagaoka, T, Shimada, Y, Hamaguchi, Y, Komura, K, Saito, E, Yanaba, K, Takehara, K, Kadono, T, Steeber, DA, Tedder, TF, and Sato, S. "The cutaneous reverse Arthus reaction requires intercellular adhesion molecule 1 and L-selectin expression." J Immunol 168.6 (March 15, 2002): 2970-2978.
PMID
11884469
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
168
Issue
6
Publish Date
2002
Start Page
2970
End Page
2978

CD19 amplification of B lymphocyte Ca2+ responses: a role for Lyn sequestration in extinguishing negative regulation.

B lymphocyte antigen receptor (BCR) signals are regulated by CD19, with BCR-induced intracellular calcium ([Ca(2+)](i)) responses enhanced by CD19 co-ligation. In this study, CD19 engagement using a dimeric anti-CD19 antibody induced [Ca(2+)](i) mobilization and significantly enhanced BCR-induced [Ca(2+)](i) responses without a requirement for CD19/BCR co-ligation. Although simultaneous CD19 and BCR engagement significantly enhanced CD19/Lyn complex formation and [Ca(2+)](i) responses, downstream tyrosine phosphorylation of CD22 and multiple other cellular proteins was inhibited, as was SHP1 recruitment to phosphorylated CD22. CD19 overexpression also enhanced BCR-induced [Ca(2+)](i) responses, but down-regulated tyrosine phosphorylation of CD22 and multiple other cellular proteins following BCR ligation. Because CD19 and Lyn expression are genetically titrated in B cells, CD19 engagement may augment BCR-induced [Ca(2+)](i) responses by sequestering the available pool of functional Lyn away from downstream negative regulatory proteins such as CD22. Consistent with this, simultaneous CD19 engagement did not further enhance the BCR-induced [Ca(2+)](i) responses of Lyn- or CD22-deficient B cells. Thus, CD19 recruitment of Lyn may preferentially activate selective signaling pathways downstream of the CD19/Lyn complex to the exclusion of other downstream regulatory and effector pathways. Other receptors may also utilize a similar strategy to regulate kinase availability and downstream intermolecular signaling.

Authors
Fujimoto, M; Poe, JC; Hasegawa, M; Tedder, TF
MLA Citation
Fujimoto, M, Poe, JC, Hasegawa, M, and Tedder, TF. "CD19 amplification of B lymphocyte Ca2+ responses: a role for Lyn sequestration in extinguishing negative regulation." J Biol Chem 276.48 (November 30, 2001): 44820-44827.
PMID
11584010
Source
pubmed
Published In
The Journal of biological chemistry
Volume
276
Issue
48
Publish Date
2001
Start Page
44820
End Page
44827
DOI
10.1074/jbc.M107559200

CD19 can regulate B lymphocyte signal transduction independent of complement activation.

B lymphocytes are critically regulated by signals transduced through the CD19-CD21 cell surface receptor complex, where complement C3d binding to CD21 supplies an already characterized ligand. To determine the extent that CD19 function is controlled by complement activation, CD19-deficient mice (that are hyporesponsive to transmembrane signals) and mice overexpressing CD19 (that are hyperresponsive) were crossed with CD21- and C3-deficient mice. Cell surface CD19 and CD21 expression were significantly affected by the loss of CD21 and C3 expression, respectively. Mature B cells from CD21-deficient littermates had approximately 36% higher cell surface CD19 expression, whereas CD21/35 expression was increased by approximately 45% on B cells from C3-deficient mice. Negative regulation of CD19 and CD21 expression by CD21 and C3, respectively, may be functionally significant because small increases in cell surface CD19 overexpression can predispose to autoimmunity. Otherwise, B cell development and function in CD19-deficient and -overexpressing mice were not significantly affected by a simultaneous loss of CD21 expression. Although CD21-deficient mice were found to express a hypomorphic cell surface CD21 protein at low levels that associated with mouse CD19, C3 deficiency did not significantly affect B cell development and function in CD19-deficient or -overexpressing mice. These results, and the severe phenotype exhibited by CD19-deficient mice compared with CD21- or C3-deficient mice, collectively demonstrate that CD19 can regulate B cell signaling thresholds independent of CD21 engagement and complement activation.

Authors
Hasegawa, M; Fujimoto, M; Poe, JC; Steeber, DA; Tedder, TF
MLA Citation
Hasegawa, M, Fujimoto, M, Poe, JC, Steeber, DA, and Tedder, TF. "CD19 can regulate B lymphocyte signal transduction independent of complement activation." J Immunol 167.6 (September 15, 2001): 3190-3200.
PMID
11544305
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
167
Issue
6
Publish Date
2001
Start Page
3190
End Page
3200

A CD19-dependent signaling pathway regulates autoimmunity in Lyn-deficient mice.

CD19 and the Src family protein tyrosine kinases (PTKs) are important regulators of intrinsic signaling thresholds in B cells. Regulation is achieved by cross-talk between Src family PTKs and CD19; Lyn is essential for CD19 phosphorylation, while CD19 establishes an Src family PTK activation loop that amplifies kinase activity. However, CD19-deficient (CD19(-/-)) B cells are hyporesponsive to transmembrane signals, while Lyn-deficient (Lyn(-/-)) B cells exhibit a hyper-responsive phenotype resulting in autoimmunity. To identify the outcome of interactions between CD19 and Src family PTKs in vivo, B cell function was examined in mice deficient for CD19 and Lyn (CD19/Lyn(-/-)). Remarkably, CD19 deficiency suppressed the hyper-responsive phenotype of Lyn(-/-) B cells and autoimmunity characterized by serum autoantibodies and immune complex-mediated glomerulonephritis in Lyn(-/-) mice. Consistent with Lyn and CD19 each regulating conventional B cell development, B1 cell development was markedly reduced by Lyn deficiency, with further reductions in the absence of CD19 expression. Tyrosine phosphorylation of Fyn and other cellular proteins induced following B cell Ag receptor ligation was dramatically reduced in CD19/Lyn(-/-) B cells relative to Lyn(-/-) B cells, while Syk phosphorylation was normal. In addition, the enhanced intracellular Ca(2+) responses following B cell Ag receptor ligation that typify Lyn deficiency were delayed by the loss of CD19 expression. BCR-induced proliferation and humoral immune responses were also markedly inhibited by CD19/Lyn deficiency. These findings demonstrate that while the CD19/Lyn amplification loop is a major regulator of signal transduction thresholds in B lymphocytes, CD19 regulation of other Src family PTKs also influences B cell function and the development of autoimmunity.

Authors
Hasegawa, M; Fujimoto, M; Poe, JC; Steeber, DA; Lowell, CA; Tedder, TF
MLA Citation
Hasegawa, M, Fujimoto, M, Poe, JC, Steeber, DA, Lowell, CA, and Tedder, TF. "A CD19-dependent signaling pathway regulates autoimmunity in Lyn-deficient mice." J Immunol 167.5 (September 1, 2001): 2469-2478.
PMID
11509585
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
167
Issue
5
Publish Date
2001
Start Page
2469
End Page
2478

Structural organization of the human MS4A gene cluster on Chromosome 11q12.

CD20, the high-affinity IgE receptor beta chain (FcepsilonRIbeta), and HTm4 are structurally related cell surface proteins expressed by hematopoietic cells. Recently, 16 novel human and mouse genes were identified that encode new members of this nascent protein family that we have named the membrane-spanning 4A gene family, with at least 12 subgroups (MS4A1-MS4A12). In the current study, we identified three additional human MS4A genes: MS4A4E, MS4A6E, and MS4A10. All family members have at least four potential transmembrane domains and N- and C-terminal cytoplasmic domains encoded by distinct exons, except MS4A6E which contains two transmembrane domains. Otherwise, the 12 currently identified MS4A genes share common structural features and similar intron/exon splice boundaries, and are clustered along an approximately 600-kb region of Chromosome 11q12. In contrast to other MS4A genes, MS4A4E, MS4A6E, and MS4A10 transcripts were rare and not detected among hematopoietic cells and most nonlymphoid tissues. Sequence polymorphisms were identified in the MS4A6E gene and common splice variants were observed for the MS4A4A, MS4A5, MS4A6A, and MS4A7 genes. Thus, the MS4A family currently includes 24 distinct human and mouse genes. Like CD20 and FcepsilonRIbeta, the 10 other human MS4A family members are likely to be components of oligomeric cell surface complexes involved in signal transduction in diverse cell lineages.

Authors
Liang, Y; Buckley, TR; Tu, L; Langdon, SD; Tedder, TF
MLA Citation
Liang, Y, Buckley, TR, Tu, L, Langdon, SD, and Tedder, TF. "Structural organization of the human MS4A gene cluster on Chromosome 11q12." Immunogenetics 53.5 (July 2001): 357-368.
PMID
11486273
Source
pubmed
Published In
Immunogenetics
Volume
53
Issue
5
Publish Date
2001
Start Page
357
End Page
368

L-Selectin is required for the development of airway hyperresponsiveness but not airway inflammation in a murine model of asthma.

BACKGROUND: Airway inflammation and airway hyperresponsiveness (AHR) are fundamental features of asthma. Migration of inflammatory cells from the circulation into the lungs is dependent on adhesion molecule interactions. The cell surface adhesion molecule L-selectin has been demonstrated to mediate leukocyte rolling on inflamed and noninflamed pulmonary endothelium. However, its role in the development of airway inflammation and AHR in asthma has not been examined. OBJECTIVE: We sought to characterize the role of L-selectin in the recruitment of inflammatory cells to the airway-lung and the development of AHR in a murine model of asthma. METHODS: An ovalbumin (OVA)-induced allergic airway disease model of asthma was applied to L-selectin-deficient (LKO) mice and C57BL/6 wild-type (WT) control mice. The development of airway inflammation was assessed by examining leukocyte influx into bronchoalveolar lavage (BAL) fluid and the lung. Total and differential BAL leukocyte counts were determined, and the immunophenotype of BAL lymphocytes was assessed by means of flow cytometry. The development of AHR was assessed by means of whole-body plethysmography. RESULTS: Airway-lung inflammation was equivalent in LKO and WT mice sensitized-challenged with OVA, as measured by total and differential BAL cell counts and histologic analysis of lung tissue. Numbers of eosinophils, neutrophils, lymphocytes, and monocytes in BAL fluid were equivalent in LKO and WT mice. However, phenotypic analysis of BAL lymphocytes demonstrated significantly reduced CD3(+) populations and increased B220(+) populations in LKO compared with WT mice (P <.05). Remarkably, despite a fulminant inflammatory response in the airway-lung in LKO mice sensitized-challenged with OVA, AHR was completely abrogated. CONCLUSION: L-selectin plays a crucial role in the development of AHR but not allergic inflammation in an animal model of asthma. L-selectin represents a potential target for novel asthma therapies specifically aimed at controlling AHR.

Authors
Fiscus, LC; Van Herpen, J; Steeber, DA; Tedder, TF; Tang, ML
MLA Citation
Fiscus, LC, Van Herpen, J, Steeber, DA, Tedder, TF, and Tang, ML. "L-Selectin is required for the development of airway hyperresponsiveness but not airway inflammation in a murine model of asthma." J Allergy Clin Immunol 107.6 (June 2001): 1019-1024.
PMID
11398079
Source
pubmed
Published In
Journal of Allergy and Clinical Immunology
Volume
107
Issue
6
Publish Date
2001
Start Page
1019
End Page
1024
DOI
10.1067/mai.2001.114703

Isolation and generation of human dendritic cells.

Dendritic cells are highly specialized antigen-presenting cells (APC), which may be isolated or generated from human blood mononuclear cells. Although mature blood dendritic cells normally represent 0.2% of human blood mononuclear cells, their frequency can be greatly increased using the cell enrichment methods described in this unit. More highly purified dendritic cell preparations can be obtained from these populations by sorting of fluorescence-labeled cells. Alternatively, dendritic cells can be generated from monocytes by culture with the appropriate cytokines, as described here. In addition, a negative selection approach is provided that may be employed to generate cell preparations that have been depleted of dendritic cells to be used for comparison in functional studies.

Authors
Tedder, TF; Jansen, PJ
MLA Citation
Tedder, TF, and Jansen, PJ. "Isolation and generation of human dendritic cells." Current protocols in immunology / edited by John E. Coligan .. [et al.] Chapter 7 (May 2001): Unit 7.32-. (Academic Article)
PMID
18432844
Source
manual
Published In
Current Protocols in Immunology
Volume
Chapter 7
Publish Date
2001
Start Page
Unit 7.32
DOI
10.1002/0471142735.im0732s23

Antibody binding to a conformation-dependent epitope induces L-selectin association with the detergent-resistant cytoskeleton.

L-Selectin mediates leukocyte rolling on endothelium and immobilized leukocytes. Its regulation has been the subject of much study, and the conformation of the molecule may play an important role in its function. Here we report that a conformational change in L-selectin, induced by an anti-lectin domain mAb (LAM1-116) and recognized by another mAb directed to a conserved epitope on L-selectin (EL-246), predisposed L-selectin to cytoskeletal association. This effect was due to direct binding of the mAb, not to overt signaling events, and was specific to LAM1-116. Nineteen other anti-L-selectin mAbs directed against the lectin, epidermal growth factor, or short consensus repeat domains lacked this activity. The induced conformational change occurred at 37 degrees C, at 4 degrees C, in the presence of sodium azide and tyrosine kinase inhibitors herbimycin A and genistein, and with soluble detergent-extracted L-selectin. In the presence of LAM1-116, EL-246 induced cytoskeletal association of L-selectin in the absence of Ab cross-linking as visualized by L-selectin staining after low dose detergent treatment of the cells. We propose that the conformational change described herein regulates L-selectin-mediated events by exposing a high avidity binding site that, when engaged, triggers association of L-selectin with the cytoskeleton, which may lead to stronger tethers with physiological ligands.

Authors
Leid, JG; Steeber, DA; Tedder, TF; Jutila, MA
MLA Citation
Leid, JG, Steeber, DA, Tedder, TF, and Jutila, MA. "Antibody binding to a conformation-dependent epitope induces L-selectin association with the detergent-resistant cytoskeleton." J Immunol 166.8 (April 15, 2001): 4899-4907.
PMID
11290767
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
166
Issue
8
Publish Date
2001
Start Page
4899
End Page
4907

L-selectin and intercellular adhesion molecule 1 mediate lymphocyte migration to the inflamed airway/lung during an allergic inflammatory response in an animal model of asthma.

T lymphocytes play a critical role in the development of allergic inflammation in asthma. Early in the allergic response, T lymphocytes migrate from the circulation into the lung to initiate and propagate airway inflammation. The adhesion molecules that mediate lymphocyte entry into inflamed lung have not been defined. This study directly examined the roles of L-selectin and intercellular adhesion molecule 1 (ICAM-1) in lymphocyte migration to the lung during an allergic inflammatory response in an animal model of asthma. Short-term (1 hour) in vivo migration assays and various combinations of adhesion molecule-deficient and wild-type mice were used. Migration of in vivo activated lymphocytes into inflamed lung was significantly greater than entry of resting lymphocytes into noninflamed lung (24.5% +/- 2.7% vs 9.5% +/- 1.3%, P =.001). Migration of activated lymphocytes into inflamed lung was inhibited by 30% in the absence of L-selectin (17.3% +/- 1.3%, P =.04), 47% in the absence of cell surface ICAM-1 (13.0% +/- 2.5%, P =.01), and 47% in the absence of endothelial ICAM-1 (13.0% +/- 2.5%, P =.01). Loss of ICAM-1 on both lymphocytes and lung endothelium inhibited lymphocyte migration by 60% (9.8% +/- 1.8%, P =.002). These findings demonstrate clear roles for both L-selectin and ICAM-1 in lymphocyte migration to the lung during an allergic inflammatory response, with ICAM-1 playing a greater role.

Authors
Keramidaris, E; Merson, TD; Steeber, DA; Tedder, TF; Tang, ML
MLA Citation
Keramidaris, E, Merson, TD, Steeber, DA, Tedder, TF, and Tang, ML. "L-selectin and intercellular adhesion molecule 1 mediate lymphocyte migration to the inflamed airway/lung during an allergic inflammatory response in an animal model of asthma." J Allergy Clin Immunol 107.4 (April 2001): 734-738.
PMID
11295667
Source
pubmed
Published In
Journal of Allergy and Clinical Immunology
Volume
107
Issue
4
Publish Date
2001
Start Page
734
End Page
738
DOI
10.1067/mai.2001.114050

CHST1 and CHST2 sulfotransferase expression by vascular endothelial cells regulates shear-resistant leukocyte rolling via L-selectin.

Sulfation is an essential component of the selectin ligands, potentially mediated by members of a new family of carbohydrate sulfotransferases. In this study, we assessed the contributions of CHST1, CHST2, CHST3, and CHST4 in producing functional L-selectin ligands. Human umbilical vein endothelial cells predominantly expressed CHST1 and CHST2 transcripts with low levels of CHST3 mRNA, while cytokine activation up-regulated CHST2 expression and induced low-level CHST4 expression. A human umbilical vein endothelial cell line, EA.hy926, displayed functional L-selectin ligands that correlated with CHST1 and CHST2 expression in the absence of CHST4 expression. Increased CHST1 or CHST2 expression by a cell line expressing low-level L-selectin ligand activity during in vitro flow chamber assays increased rolling leukocyte numbers, reduced rolling velocities, and enhanced leukocyte rolling under higher shear stresses. These results suggest that CHST1 and CHST2 contribute to the generation of optimal L-selectin ligands in vascular endothelial cells at sites of inflammation.

Authors
Li, X; Tu, L; Murphy, PG; Kadono, T; Steeber, DA; Tedder, TF
MLA Citation
Li, X, Tu, L, Murphy, PG, Kadono, T, Steeber, DA, and Tedder, TF. "CHST1 and CHST2 sulfotransferase expression by vascular endothelial cells regulates shear-resistant leukocyte rolling via L-selectin." J Leukoc Biol 69.4 (April 2001): 565-574.
PMID
11310842
Source
pubmed
Published In
Journal of leukocyte biology
Volume
69
Issue
4
Publish Date
2001
Start Page
565
End Page
574

L-selectin deficiency in MRL-1pr mice eliminates lymphadenopathy and reduces autoimmunity

Authors
Steeber, DA; Zhang, XQ; Fujimoto, Y; Poe, JC; Pisetsky, DS; Tedder, TF
MLA Citation
Steeber, DA, Zhang, XQ, Fujimoto, Y, Poe, JC, Pisetsky, DS, and Tedder, TF. "L-selectin deficiency in MRL-1pr mice eliminates lymphadenopathy and reduces autoimmunity." FASEB JOURNAL 15.5 (March 8, 2001): A1059-A1059.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
5
Publish Date
2001
Start Page
A1059
End Page
A1059

CD19 expression influences the incidence and severity of lymphomas in Emu-c-myc transgenic mice

Authors
Poe, JC; Tedder, TF
MLA Citation
Poe, JC, and Tedder, TF. "CD19 expression influences the incidence and severity of lymphomas in Emu-c-myc transgenic mice." FASEB JOURNAL 15.5 (March 8, 2001): A1207-A1207.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
5
Publish Date
2001
Start Page
A1207
End Page
A1207

Expression of L-selectin or ICAM-1 is required for a shift from delayed-type response (DTR) to immediate-type hypersensitivity response (IHR) in repeated elicitation of contact hypersensitivity

Authors
Shimada, Y; Takehara, K; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Shimada, Y, Takehara, K, Steeber, DA, Tedder, TF, and Sato, S. "Expression of L-selectin or ICAM-1 is required for a shift from delayed-type response (DTR) to immediate-type hypersensitivity response (IHR) in repeated elicitation of contact hypersensitivity." FASEB JOURNAL 15.5 (March 8, 2001): A715-A715.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
5
Publish Date
2001
Start Page
A715
End Page
A715

CD19 loss inhibits the development of autoimmunity in Lyn-deficient mice

Authors
Hasegawa, M; Fujimoto, M; Lowell, CA; Tedder, TF
MLA Citation
Hasegawa, M, Fujimoto, M, Lowell, CA, and Tedder, TF. "CD19 loss inhibits the development of autoimmunity in Lyn-deficient mice." FASEB JOURNAL 15.5 (March 8, 2001): A1060-A1060.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
5
Publish Date
2001
Start Page
A1060
End Page
A1060

Synergistic and independent roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction

Authors
Fujimoto, M; Poe, JC; Satterthwaite, AB; Wahl, ML; Witte, ON; Tedder, TF
MLA Citation
Fujimoto, M, Poe, JC, Satterthwaite, AB, Wahl, ML, Witte, ON, and Tedder, TF. "Synergistic and independent roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction." FASEB JOURNAL 15.4 (March 7, 2001): A706-A706.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
4
Publish Date
2001
Start Page
A706
End Page
A706

Dendritic cell CD83 provides a progression signal required for CD4+T cell positive selection in the thymus

Authors
Fujimoto, K; Tu, L; Miller, AS; Bock, C; Fujimoto, M; Steeber, DA; Doyle, C; Tedder, TF
MLA Citation
Fujimoto, K, Tu, L, Miller, AS, Bock, C, Fujimoto, M, Steeber, DA, Doyle, C, and Tedder, TF. "Dendritic cell CD83 provides a progression signal required for CD4+T cell positive selection in the thymus." FASEB JOURNAL 15.4 (March 7, 2001): A672-A672.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
4
Publish Date
2001
Start Page
A672
End Page
A672

Identification of a CD20, Fc epsilon R1 beta and HTm4 related gene family: Sixteen new MS4A family members expressed in human and mouse

Authors
Liang, YH; Tedder, TF
MLA Citation
Liang, YH, and Tedder, TF. "Identification of a CD20, Fc epsilon R1 beta and HTm4 related gene family: Sixteen new MS4A family members expressed in human and mouse." FASEB JOURNAL 15.4 (March 7, 2001): A713-A713.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
4
Publish Date
2001
Start Page
A713
End Page
A713

Identification of a CD20-, FcepsilonRIbeta-, and HTm4-related gene family: sixteen new MS4A family members expressed in human and mouse.

CD20, high-affinity IgE receptor beta chain (FcepsilonRIbeta), and HTm4 are structurally related cell-surface proteins expressed by hematopoietic cells. In the current study, 16 novel human and mouse genes that encode new members of this nascent protein family were identified. All family members had at least four potential membrane-spanning domains, with N- and C-terminal cytoplasmic domains. This family was therefore named the membrane-spanning 4A gene family, with at least 12 subgroups (MS4A1 through MS4A12) currently representing at least 21 distinct human and mouse proteins. Each family member had unique patterns of expression among hematopoietic cells and nonlymphoid tissues. Four of the 6 human MS4A genes identified in this study mapped to chromosome 11q12-q13.1 along with CD20, FcepsilonRIbeta, and HTm4. Thus, like CD20 and FcepsilonRIbeta, the other MS4A family members are likely to be components of oligomeric cell surface complexes that serve diverse signal transduction functions.

Authors
Liang, Y; Tedder, TF
MLA Citation
Liang, Y, and Tedder, TF. "Identification of a CD20-, FcepsilonRIbeta-, and HTm4-related gene family: sixteen new MS4A family members expressed in human and mouse." Genomics 72.2 (March 1, 2001): 119-127.
PMID
11401424
Source
pubmed
Published In
Genomics
Volume
72
Issue
2
Publish Date
2001
Start Page
119
End Page
127
DOI
10.1006/geno.2000.6472

Lupus-specific antiribonucleoprotein B cell tolerance in nonautoimmune mice is maintained by differentiation to B-1 and governed by B cell receptor signaling thresholds.

Systemic lupus erythematosus is an autoimmune disease characterized by the presence of autoantibodies. One of the unique targets of the immune system in systemic lupus erythematosus is Sm, a ribonucleoprotein present in all cells. To understand the regulation of B cells specific to the Sm Ag in normal mice, we have generated an Ig H chain transgenic mouse (2-12H Tg). 2-12H Tg mice produce B cells specific for the Sm that remain tolerant due to ignorance. We demonstrate here that anti-Sm B cells of 2-12H Tg mice can differentiate into Sm-specific peritoneal B-1 cells that remain tolerant. Differentiation to B-1 and tolerance are governed by the strength of B cell receptor signaling, since manipulations of the B cell receptor coreceptors CD19 and CD22 affect anti-Sm B cell differentiation and autoantibody production. These results suggest a differentiation scheme in which peripheral ignorance to Sm is maintained in mice by the differentiation of anti-Sm B cells to B-1 cells that have increased activation thresholds.

Authors
Qian, Y; Santiago, C; Borrero, M; Tedder, TF; Clarke, SH
MLA Citation
Qian, Y, Santiago, C, Borrero, M, Tedder, TF, and Clarke, SH. "Lupus-specific antiribonucleoprotein B cell tolerance in nonautoimmune mice is maintained by differentiation to B-1 and governed by B cell receptor signaling thresholds." J Immunol 166.4 (February 15, 2001): 2412-2419.
PMID
11160300
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
166
Issue
4
Publish Date
2001
Start Page
2412
End Page
2419

CD19, CD21, and CD22: multifaceted response regulators of B lymphocyte signal transduction.

B lymphocyte development and function depend upon the activity of intrinsic and B cell antigen receptor (BCR)-induced signals. These signals are interpreted, amplified, fine-tuned, or suppressed through the precise actions of specialized cell surface coreceptors, or "response regulators," that inform B cells of their extracellular environment. Important cell surface response regulators include the CD19/CD21 complex, CD22, and CD72. CD19 establishes a novel Src-family protein tyrosine kinase (PTK) amplification loop that regulates basal signaling thresholds and intensifies Src-family PTK activation following BCR ligation. In turn, CD22 limits the intensity of CD19-dependent, BCR-generated signals through the recruitment of potent phosphotyrosine and phosphoinositide phosphatases. Herein we discuss our current understanding of how CD19/CD21 and CD22 govern the emergence and intensity of BCR-mediated signals, and how alterations in these tightly controlled regulatory activities contribute to autoimmunity in mice and humans.

Authors
Poe, JC; Hasegawa, M; Tedder, TF
MLA Citation
Poe, JC, Hasegawa, M, and Tedder, TF. "CD19, CD21, and CD22: multifaceted response regulators of B lymphocyte signal transduction." Int Rev Immunol 20.6 (2001): 739-762. (Review)
PMID
11913948
Source
pubmed
Published In
International Reviews of Immunology (Informa)
Volume
20
Issue
6
Publish Date
2001
Start Page
739
End Page
762

A role for CD21/CD35 and CD19 in responses to acute septic peritonitis: a potential mechanism for mast cell activation.

Although it is now appreciated that mast cell-mediated release of TNF-alpha is critical for resolution of acute septic peritonitis, questions remain as to how mast cells are activated upon peritoneal bacterial infection. Clues to how this may occur have been derived from earlier studies by Prodeus et al. in which complement proteins C3 and C4 were shown to be required for survival following cecal ligation and puncture (CLP), a model for acute septic peritonitis. To evaluate the mechanism for mast cell activation in the CLP model, complement receptor CD21/CD35-deficient mice (Cr2(null)) were examined in the present study. Along with CD19-deficient (CD19(null)) mice, these animals exhibit decreased survival following CLP compared with wild-type littermates. Injection of IgM before CLP does not change survival rates for Cr2(null) mice and only partially improves survival of CD19(null) mice, implicating CD21/CD35 and CD19 in mast cell activation. Interestingly, early TNF-alpha release is also impaired in Cr2(null) and CD19(null) animals, suggesting that these molecules directly affect mast cell activation. Cr2(null) and CD19(null) mice demonstrate an impairment in neutrophil recruitment and a corresponding increase in bacterial load. Examination of peritoneal mast cells by flow cytometry and confocal microscopy reveals the expression and colocalization of CD21/CD35 and CD19. Taken together, these findings suggest that the engagement of complement receptors CD21/CD35 along with CD19 on the mast cell surface by C3 fragments may be necessary for the full expression of mast cell activation in the CLP model.

Authors
Gommerman, JL; Oh, DY; Zhou, X; Tedder, TF; Maurer, M; Galli, SJ; Carroll, MC
MLA Citation
Gommerman, JL, Oh, DY, Zhou, X, Tedder, TF, Maurer, M, Galli, SJ, and Carroll, MC. "A role for CD21/CD35 and CD19 in responses to acute septic peritonitis: a potential mechanism for mast cell activation." J Immunol 165.12 (December 15, 2000): 6915-6921.
PMID
11120817
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
165
Issue
12
Publish Date
2000
Start Page
6915
End Page
6921

The c-Abl tyrosine kinase is regulated downstream of the B cell antigen receptor and interacts with CD19.

c-Abl is a nonreceptor tyrosine kinase that we have recently linked to growth factor receptor signaling. The c-Abl kinase is ubiquitously expressed and localizes to the cytoplasm, plasma membrane, cytoskeleton, and nucleus. Thus, c-Abl may regulate signaling processes in multiple subcellular compartments. Targeted deletion or mutation of c-Abl in mice results in a variety of phenotypes, including splenic and thymic atrophy and lymphopenia. Additionally, lymphocytes isolated from specific compartments of c-Abl mutant mice have reduced responses to a variety of stimuli and an increased susceptibility to apoptosis following growth factor deprivation. Despite these observations, little is known regarding the signaling mechanisms responsible for these phenotypes. We report here that splenic B cells from c-Abl-deficient mice are hyporesponsive to the proliferative effects of B cell Ag receptor (BCR) stimulation. The c-Abl kinase activity and protein levels are elevated in the cytosol following activation of the BCR in B cell lines. We show that c-Abl associates with and phosphorylates the BCR coreceptor CD19, and that c-Abl and CD19 colocalize in lipid membrane rafts. These data suggest a role for c-Abl in the regulation of B cell proliferation downstream of the BCR, possibly through interactions with CD19.

Authors
Zipfel, PA; Grove, M; Blackburn, K; Fujimoto, M; Tedder, TF; Pendergast, AM
MLA Citation
Zipfel, PA, Grove, M, Blackburn, K, Fujimoto, M, Tedder, TF, and Pendergast, AM. "The c-Abl tyrosine kinase is regulated downstream of the B cell antigen receptor and interacts with CD19." J Immunol 165.12 (December 15, 2000): 6872-6879.
PMID
11120811
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
165
Issue
12
Publish Date
2000
Start Page
6872
End Page
6879

Quantitative genetic variation in CD19 expression correlates with autoimmunity.

Signaling thresholds influence the balance between humoral immunity and autoimmunity. Cell surface CD19 regulates intrinsic and Ag receptor-induced B lymphocyte signaling thresholds, and transgenic mice that overexpress CD19 by 3-fold generate spontaneous autoantibodies in a genetic background not associated with autoimmunity. To quantify the extent that genetically determined differences in expression of a single cell surface molecule can influence autoantibody production, we have assessed autoimmunity in a C57BL/6-transgenic mouse line with subtle 15-29% increases in CD19 cell surface expression (CD19 transgenic). Antinuclear Abs, especially anti-spindle pole Abs, rheumatoid factor, and autoantibodies for ssDNA, dsDNA, and histone were produced in these transgenic mice, but not littermate controls. This demonstrates that small changes in CD19 expression can induce autoantibody production. Remarkably, similar changes in CD19 expression were found on B cells from patients with systemic sclerosis, a multisystem disorder of connective tissue with autoantibody production. CD19 density on blood B cells from systemic sclerosis patients was significantly ( approximately 20%) higher compared with normal individuals, whereas CD20, CD22, and CD40 expression were normal. These results suggest that modest changes in the expression or function of regulatory molecules such as CD19 may shift the balance between tolerance and immunity to autoimmunity. Thereby autoimmune disease may result from a collection of subtle multigenic alterations that could include incremental density changes in cell surface signaling molecules.

Authors
Sato, S; Hasegawa, M; Fujimoto, M; Tedder, TF; Takehara, K
MLA Citation
Sato, S, Hasegawa, M, Fujimoto, M, Tedder, TF, and Takehara, K. "Quantitative genetic variation in CD19 expression correlates with autoimmunity." J Immunol 165.11 (December 1, 2000): 6635-6643.
PMID
11086109
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
165
Issue
11
Publish Date
2000
Start Page
6635
End Page
6643

Decreased expression levels of L-selectin on subsets of leucocytes and increased serum L-selectin in severe psoriasis.

L-selectin is a leucocyte adhesion molecule involved in leucocyte interactions with vascular endothelial cells. Following leucocyte activation L-selectin is endoproteolytically released from the cell surface. To assess whether psoriasis vulgaris results in systemic leucocyte activation, we examined expression levels of L-selectin on subsets of peripheral blood leucocytes from patients with psoriasis (n = 25) and normal control subjects. Serum levels of soluble L-selectin were quantified by ELISA in patients with psoriasis (n = 75), pustulosis palmaris et plantaris, and contact dermatitis, as well as normal control subjects. Psoriasis severity was evaluated by psoriasis area and severity index (PASI). L-selectin expression levels on CD4+ T cells, B cells, monocytes, and neutrophils from patients with severe-type psoriasis (PASI > or = 15) was significantly decreased compared with leucocytes from normal control subjects. Furthermore, L-selectin expression on CD4+ T cells showed good inverse correlation with PASI scores. Monocyte L-selectin expression was restored when the skin lesions of psoriasis were remitted. The frequencies of L-selectin+ CD4+ T cells or L-selectin+ CD8+ T cells from patients with psoriasis were almost normal. Serum L-selectin levels in patients with severe-type psoriasis were significantly higher than those in normal control subjects. These results suggest that subsets of leucocytes may be activated in psoriasis, and that L-selectin expression levels on some leucocyte subsets, especially CD4+ T cells, tend to correlate with disease severity of psoriasis.

Authors
Inaoki, M; Sato, S; Shimada, Y; Kawara, S; Steeber, DA; Tedder, TF; Takehara, K
MLA Citation
Inaoki, M, Sato, S, Shimada, Y, Kawara, S, Steeber, DA, Tedder, TF, and Takehara, K. "Decreased expression levels of L-selectin on subsets of leucocytes and increased serum L-selectin in severe psoriasis." Clin Exp Immunol 122.3 (December 2000): 484-492.
PMID
11122259
Source
pubmed
Published In
Clinical & Experimental Immunology
Volume
122
Issue
3
Publish Date
2000
Start Page
484
End Page
492

Transcription factor NF-kappaB regulates inducible CD83 gene expression in activated T lymphocytes.

The immunoglobulin superfamily member CD83 is expressed on the surface of mature dendritic cells that present processed antigens to T lymphocytes. In addition, T cells acquire CD83 expression following mitogenic stimulation in vitro. Here we report two lines of evidence demonstrating that this inducible lymphocyte response is genetically programmed by transcription factor NF-kappaB and contingent upon proteolytic breakdown of its cytoplasmic inhibitor IkappaBalpha. First, signal-dependent induction of CD83 mRNA expression is blocked in both transformed and primary T cells harboring a degradation-resistant mutant of IkappaBalpha that constitutively represses NF-kappaB. Second, as revealed in gel retardation assays, the IkappaBalpha constitutive repressor prevents the inducible interaction of NF-kappaB with consensus recognition sites identified in the CD83 promoter. Given that IkappaBalpha is functionally coupled to the T-cell antigen receptor, these findings suggest that the downstream transcription unit for CD83 is triggered by NF-kappaB during an adaptive immune response.

Authors
McKinsey, TA; Chu, Z; Tedder, TF; Ballard, DW
MLA Citation
McKinsey, TA, Chu, Z, Tedder, TF, and Ballard, DW. "Transcription factor NF-kappaB regulates inducible CD83 gene expression in activated T lymphocytes." Mol Immunol 37.12-13 (August 2000): 783-788.
PMID
11275263
Source
pubmed
Published In
Molecular Immunology
Volume
37
Issue
12-13
Publish Date
2000
Start Page
783
End Page
788

Delayed wound healing in the absence of intercellular adhesion molecule-1 or L-selectin expression.

Inflammatory cells play a crucial role in wound healing, but the role of adhesion molecules including L-selectin and intercellular adhesion molecule-1 (ICAM-1) is not known in this process. We examined skin wound repair of excisional wounds in mice lacking L-selectin, ICAM-1, or both. The loss of ICAM-1 inhibited wound healing, keratinocyte migration from the edges of the wound toward the center, and granulation tissue formation. By contrast, L-selectin deficiency alone did not affect any of these parameters. However, the loss of both L-selectin and ICAM-1 resulted in inhibition of keratinocyte migration and granulation tissue formation beyond those caused by loss of ICAM-1 alone. Treatment of platelet-derived growth factor to the wounds normalized delayed wound healing in ICAM-1(-/-) mice, but not in L-selectin/ICAM-1(-/-) mice. Therefore, although ICAM-1 contributes to wound repair to a greater extent than L-selectin, a role for L-selectin was revealed in the absence of ICAM-1. The impaired wound repair was associated with reduced infiltration of neutrophils and macrophages in ICAM-1(-/-) and L-selectin/ICAM-1(-/-) mice. These results demonstrate a distinct role of ICAM-1 and L-selectin in wound healing and that the delayed wound healing in the absence of these molecules is likely because of decreased leukocyte accumulation into the wound site.

Authors
Nagaoka, T; Kaburagi, Y; Hamaguchi, Y; Hasegawa, M; Takehara, K; Steeber, DA; Tedder, TF; Sato, S
MLA Citation
Nagaoka, T, Kaburagi, Y, Hamaguchi, Y, Hasegawa, M, Takehara, K, Steeber, DA, Tedder, TF, and Sato, S. "Delayed wound healing in the absence of intercellular adhesion molecule-1 or L-selectin expression." Am J Pathol 157.1 (July 2000): 237-247.
PMID
10880393
Source
pubmed
Published In
The American journal of pathology
Volume
157
Issue
1
Publish Date
2000
Start Page
237
End Page
247
DOI
10.1016/S0002-9440(10)64534-8

CD19 regulates Src family protein tyrosine kinase activation in B lymphocytes through processive amplification.

CD19 regulates constitutive and antigen receptor-induced signaling thresholds in B lymphocytes through its unique cytoplasmic domain. Herein, we demonstrate a novel molecular mechanism where interactions between CD19 and Lyn amplify basal and antigen receptor-induced Src family kinase activation. Lyn expression was required for CD19 tyrosine phosphorylation in primary B cells. Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation. In vivo, CD19 deficiency impaired, and CD19 overexpression enhanced, Lyn kinase activity. Thus, CD19 functions as a specialized adapter protein for the amplification of Src family kinases that is crucial for intrinsic and antigen receptor-induced signal transduction.

Authors
Fujimoto, M; Fujimoto, Y; Poe, JC; Jansen, PJ; Lowell, CA; DeFranco, AL; Tedder, TF
MLA Citation
Fujimoto, M, Fujimoto, Y, Poe, JC, Jansen, PJ, Lowell, CA, DeFranco, AL, and Tedder, TF. "CD19 regulates Src family protein tyrosine kinase activation in B lymphocytes through processive amplification." Immunity 13.1 (July 2000): 47-57.
PMID
10933394
Source
pubmed
Published In
Immunity
Volume
13
Issue
1
Publish Date
2000
Start Page
47
End Page
57

CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux.

CD22 is a cell surface molecule that regulates signal transduction in B lymphocytes. Tyrosine-phosphorylated CD22 recruits numerous cytoplasmic effector molecules including SHP-1, a potent phosphotyrosine phosphatase that down-regulates B cell antigen receptor (BCR)- and CD19-generated signals. Paradoxically, B cells from CD22-deficient mice generate augmented intracellular calcium responses following BCR ligation, yet proliferation is decreased. To understand further the mechanisms through which CD22 regulates BCR-dependent calcium flux and proliferation, interactions between CD22 and effector molecules involved in these processes were assessed. The adapter proteins Grb2 and Shc were found to interact with distinct and specific regions of the CD22 cytoplasmic domain. Src homology-2 domain-containing inositol polyphosphate-5'-phosphatase (SHIP) also bound phosphorylated CD22, but binding required an intact CD22 cytoplasmic domain. All three molecules were bound to CD22 when isolated from BCR-stimulated splenic B cells, indicating the formation of a CD22.Grb2.Shc.SHIP quaternary complex. Therefore, SHIP associating with CD22 may be important for SHIP recruitment to the cell surface where it negatively regulates calcium influx. Although augmented calcium responses in CD22-deficient mice should facilitate enhanced c-Jun N-terminal kinase (JNK) activation, BCR ligation did not induce JNK activation in CD22-deficient B cells. These data demonstrate that CD22 functions as a molecular "scaffold" that specifically coordinates the docking of multiple effector molecules, in addition to SHP-1, in a context necessary for BCR-dependent SHIP activity and JNK stimulation.

Authors
Poe, JC; Fujimoto, M; Jansen, PJ; Miller, AS; Tedder, TF
MLA Citation
Poe, JC, Fujimoto, M, Jansen, PJ, Miller, AS, and Tedder, TF. "CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux." J Biol Chem 275.23 (June 9, 2000): 17420-17427.
PMID
10748054
Source
pubmed
Published In
The Journal of biological chemistry
Volume
275
Issue
23
Publish Date
2000
Start Page
17420
End Page
17427
DOI
10.1074/jbc.M001892200

A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase.

Modifier screens have been powerful genetic tools to define signaling pathways in lower organisms. The identification of modifier loci in mice has begun to allow a similar dissection of mammalian signaling pathways. Transgenic mice (Btk(lo)) expressing 25% of endogenous levels of Bruton's tyrosine kinase (Btk) have B cell functional responses between those of wild-type and Btk(-/-) mice. We asked whether reduced dosage or complete deficiency of genes previously implicated as Btk regulators would modify the Btk(lo) phenotype. We used two independent assays of Btk-dependent B cell function. Proliferative response to B cell antigen receptor cross-linking in vitro was chosen as an example of a relatively simple, well-defined signaling system. In vivo response to type II T-independent antigens (TI-II) measures complex interactions among multiple cell types over time and may identify additional Btk pathways. All modifiers identified differentially affected these two assays, indicating that Btk mediates these processes via distinct mechanisms. Loss of Lyn, PTEN (phosphatase and tensin homolog), or SH2-containing inositol phosphatase suppressed the Btk(lo) phenotype in vitro but not in vivo, whereas CD19 and the p85alpha form of phosphoinositide 3-kinase behaved as Btk(lo) enhancers in vivo but not in vitro. Effects of Lyn, PTEN, or p85alpha haploinsufficiency were observed. Haploinsufficiency or complete deficiency of protein kinase C beta, Fyn, CD22, Galphaq, or Galpha11 had no detectable effect on the function of Btk(lo) B cells. A transgenic system creating a reduction in dosage of Btk can therefore be used to identify modifier loci that affect B cell responses and quantitatively rank their contribution to Btk-mediated processes.

Authors
Satterthwaite, AB; Willis, F; Kanchanastit, P; Fruman, D; Cantley, LC; Helgason, CD; Humphries, RK; Lowell, CA; Simon, M; Leitges, M; Tarakhovsky, A; Tedder, TF; Lesche, R; Wu, H; Witte, ON
MLA Citation
Satterthwaite, AB, Willis, F, Kanchanastit, P, Fruman, D, Cantley, LC, Helgason, CD, Humphries, RK, Lowell, CA, Simon, M, Leitges, M, Tarakhovsky, A, Tedder, TF, Lesche, R, Wu, H, and Witte, ON. "A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase." Proc Natl Acad Sci U S A 97.12 (June 6, 2000): 6687-6692.
PMID
10829070
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
97
Issue
12
Publish Date
2000
Start Page
6687
End Page
6692
DOI
10.1073/pnas.110146697

Clonal dominance during humoral immune responses is predominantly regulated by signal transduction thresholds rather than antigen receptor affinity

Authors
Hasegawa, M; Kim, E; Inaoki, M; Miller, A; Chen, Z; Takahashi, Y; Kelsoe, G; Tedder, TF
MLA Citation
Hasegawa, M, Kim, E, Inaoki, M, Miller, A, Chen, Z, Takahashi, Y, Kelsoe, G, and Tedder, TF. "Clonal dominance during humoral immune responses is predominantly regulated by signal transduction thresholds rather than antigen receptor affinity." FASEB JOURNAL 14.6 (April 20, 2000): A962-A962.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
14
Issue
6
Publish Date
2000
Start Page
A962
End Page
A962

CD22 forms a complex with SHIP, Grb2 and Shc: Pathways for CD22 regulation of B lymphocyte antigen receptor-induced calcium flux

Authors
Poe, JC; Fujimoto, M; Tedder, TF
MLA Citation
Poe, JC, Fujimoto, M, and Tedder, TF. "CD22 forms a complex with SHIP, Grb2 and Shc: Pathways for CD22 regulation of B lymphocyte antigen receptor-induced calcium flux." FASEB JOURNAL 14.6 (April 20, 2000): A969-A969.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
14
Issue
6
Publish Date
2000
Start Page
A969
End Page
A969

CD19 is a specialized transmembrane adapter protein that amplifies Src-family protein kinase activation

Authors
Tedder, TF; Fujimoto, Y; Poe, JC; Lowell, CA; DeFranco, AL; Fujimoto, M
MLA Citation
Tedder, TF, Fujimoto, Y, Poe, JC, Lowell, CA, DeFranco, AL, and Fujimoto, M. "CD19 is a specialized transmembrane adapter protein that amplifies Src-family protein kinase activation." FASEB JOURNAL 14.6 (April 20, 2000): A969-A969.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
14
Issue
6
Publish Date
2000
Start Page
A969
End Page
A969

Characterization of novel L-selectin ligands expressed by vascular endothelial cells.

Authors
Murphy, PG; Tu, LL; Li, X; Steeber, DA; Tedder, TF
MLA Citation
Murphy, PG, Tu, LL, Li, X, Steeber, DA, and Tedder, TF. "Characterization of novel L-selectin ligands expressed by vascular endothelial cells." FASEB JOURNAL 14.6 (April 20, 2000): A1145-A1145.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
14
Issue
6
Publish Date
2000
Start Page
A1145
End Page
A1145

Decreased expression levels of L-selectin on subsets of leukocytes in severe psoriasis.

Authors
Inaoki, M; Sato, S; Shimada, Y; Kawara, S; Steeber, DA; Tedder, TF; Takehara, K
MLA Citation
Inaoki, M, Sato, S, Shimada, Y, Kawara, S, Steeber, DA, Tedder, TF, and Takehara, K. "Decreased expression levels of L-selectin on subsets of leukocytes in severe psoriasis." FASEB JOURNAL 14.6 (April 20, 2000): A1147-A1147.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
14
Issue
6
Publish Date
2000
Start Page
A1147
End Page
A1147

CHST1 and CHST2 sulfotransferase expression by vascular endothelial cells regulates shear-resistant leukocyte rolling via L-selectin

Authors
Li, X; Tu, L; Murphy, PG; Steeber, DA; Tedder, TF
MLA Citation
Li, X, Tu, L, Murphy, PG, Steeber, DA, and Tedder, TF. "CHST1 and CHST2 sulfotransferase expression by vascular endothelial cells regulates shear-resistant leukocyte rolling via L-selectin." FASEB JOURNAL 14.6 (April 20, 2000): A1145-A1145.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
14
Issue
6
Publish Date
2000
Start Page
A1145
End Page
A1145

Soluble L-selectin is present in mouse and human sera at comparable levels

Authors
Steeber, DA; Tu, L; Zhang, XQ; Tedder, TF
MLA Citation
Steeber, DA, Tu, L, Zhang, XQ, and Tedder, TF. "Soluble L-selectin is present in mouse and human sera at comparable levels." FASEB JOURNAL 14.6 (April 20, 2000): A1145-A1145.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
14
Issue
6
Publish Date
2000
Start Page
A1145
End Page
A1145

Blockade of L-selectin attenuates reperfusion injury in a rat model.

Ischemia/reperfusion (I/R) injury appears to be a significant neutrophil-dependent component and may be ameliorated by blocking leukocyte-endothelial adhesion. Using a rat extensor digitorum longus (EDL) muscle model, the present study tested the hypothesis that in vivo administration of the function-blocking monoclonal antibody (mAb) LAM1-116 which recognizes L-selectin, a cell-surface adhesion receptor, could decrease I/R injury. In 46 rats, one EDL served as a normal control and the opposite EDL underwent 3 hr of ischemia followed by 3 hr of reperfusion after pretreatment with LAM1-116 mAb, control IgG, or saline. Myeloperoxidase (MPO) activity showed only a two-fold increase from normal in LAM1-116-treated I/R EDL while a 27-fold increase occurred in the IgG2a and saline groups, with a statistically significant (p < 0.001) difference. A significantly (p < 0.05) lower wet weight ratio, improved fatigue contractile force, and less neutrophil infiltration were found in LAM1-116-treated EDL, when compared to those in control IgG- or saline-treated EDL. The results indicate that blockade of L-selectin by LAM1-116 mAb can effectively reduce neutrophil infiltration in reperfused skeletal muscle, thereby decreasing tissue edema and improving muscle fatigue contractile force. These findings may be important in understanding I/R injury.

Authors
Yan, ZQ; Bolognesi, MP; Steeber, DA; Tedder, TF; Chen, LE; Seaber, AV; Urbaniak, JR
MLA Citation
Yan, ZQ, Bolognesi, MP, Steeber, DA, Tedder, TF, Chen, LE, Seaber, AV, and Urbaniak, JR. "Blockade of L-selectin attenuates reperfusion injury in a rat model." J Reconstr Microsurg 16.3 (April 2000): 227-233.
PMID
10803628
Source
pubmed
Published In
Journal of Reconstructive Microsurgery
Volume
16
Issue
3
Publish Date
2000
Start Page
227
End Page
233

Germline sequences of V(H)7183 gene family members in C57BL/6 mice demonstrate natural selection of particular sequences during recent evolution.

Authors
Langdon, SD; Inaioki, M; Kelsoe, G; Tedder, TF
MLA Citation
Langdon, SD, Inaioki, M, Kelsoe, G, and Tedder, TF. "Germline sequences of V(H)7183 gene family members in C57BL/6 mice demonstrate natural selection of particular sequences during recent evolution." Immunogenetics 51.3 (March 2000): 241-245.
PMID
10752635
Source
pubmed
Published In
Immunogenetics
Volume
51
Issue
3
Publish Date
2000
Start Page
241
End Page
245

CD19 and CD22 regulate a B lymphocyte signal transduction pathway that contributes to autoimmunity.

The fate of B lymphocytes is dependent on intrinsic and B cell antigen receptor (BCR)-induced signals. These signals are modified and interpreted by other cell-surface molecules such as CD19 and CD22 that govern mature B cell activation. This review assesses our current understanding of how CD19 and CD22 regulate B lymphocyte signaling and how alterations in these response-regulators contribute to autoimmunity in mice and humans. We propose that CD19 functions as a specialized adapter protein that regulates B lymphocyte signaling and autoantibody production. Overexpression of CD19 by B cells in systemic sclerosis patients correlates with autoantibody production and transgenic mice that overexpress CD19 produce similar autoantibodies. CD19 establishes a novel Src-family kinase activation loop that regulates basal signal transduction thresholds in resting B cells and amplifies Src-family kinase activation following BCR ligation. Reciprocally, CD22 is a potent regulator of CD19 function. These observations provide insight into how CD19 and CD22 govern the molecular ordering and intensity of signals transduced in B cells that may contribute to autoimmunity.

Authors
Tedder, TF; Sato, S; Poe, JC; Fujimoto, M
MLA Citation
Tedder, TF, Sato, S, Poe, JC, and Fujimoto, M. "CD19 and CD22 regulate a B lymphocyte signal transduction pathway that contributes to autoimmunity." Keio J Med 49.1 (March 2000): 1-13.
PMID
10750375
Source
pubmed
Published In
The Keio journal of medicine
Volume
49
Issue
1
Publish Date
2000
Start Page
1
End Page
13

Adhesion molecule cascades direct lymphocyte recirculation and leukocyte migration during inflammation.

Leukocyte interactions with vascular endothelium are highly orchestrated processes that include the capture of free-flowing leukocytes from the blood with subsequent leukocyte rolling, arrest, firm adhesion, and ensuing diapedesis. These interactions occur under high shear stresses within venules and depend on multiple families of adhesion molecules. Many of the adhesion molecules involved are now identified. In addition, precise mechanisms underlying their regulation and our understanding of how different families of adhesion molecules work together is becoming clearer. Specifically, leukocyte/endothelial cell interactions such as capture, rolling, and firm adhesion can no longer be viewed as occurring in discrete steps mediated by individual families of adhesion molecules, but rather as a series of overlapping synergistic interactions among adhesion molecules resulting in an adhesion cascade. Although long thought to be mediated by distinct adhesion pathways, overlapping adhesion cascades mediate normal lymphocyte recirculation to peripheral lymphoid tissues and inflammation-induced leukocyte migration. These cascades thereby direct leukocyte migration, which is essential for the generation of effective inflammatory responses and the development of rapid immune responses.

Authors
Steeber, DA; Tedder, TF
MLA Citation
Steeber, DA, and Tedder, TF. "Adhesion molecule cascades direct lymphocyte recirculation and leukocyte migration during inflammation." Immunol Res 22.2-3 (2000): 299-317. (Review)
PMID
11339364
Source
pubmed
Published In
Immunologic Research
Volume
22
Issue
2-3
Publish Date
2000
Start Page
299
End Page
317
DOI
10.1385/IR:22:2-3:299

Immunology at Duke.

Authors
Ward, FE; Tedder, TF
MLA Citation
Ward, FE, and Tedder, TF. "Immunology at Duke." Immunol Res 22.2-3 (2000): 67-69.
PMID
11339366
Source
pubmed
Published In
Immunologic Research
Volume
22
Issue
2-3
Publish Date
2000
Start Page
67
End Page
69
DOI
10.1385/IR:22:2-3:67

CD19 regulates intrinsic B lymphocyte signal transduction and activation through a novel mechanism of processive amplification.

The fate of B lymphocytes is dependent on intrinsic and B cell antigen receptor (BCR)-induced signals. These signals are interpreted and modified by response regulators such as CD19 that govern mature B cell activation. The current understanding of how CD19 governs B lymphocyte signaling is outlined in this review. Primarily, CD19 establishes a novel Src-family kinase amplification loop that regulates basal signal transduction thresholds in resting B cells. Moreover, CD19 amplifies Src-family kinase activation following BCR ligation. CD19 amplification of Lyn activity leads to processive phosphorylation of CD19 and downstream substrates including CD22. Phosphorylated CD19 recruits other effector molecules including Vav, Grb2, phosphoinositide 3-kinase, phospholipase Cgamma2, and c-Abl, which may contribute to CD19 regulation of B cell function. CD19/Lyn complex formation also regulates phosphorylation of CD22 and FcgammaRIIB, which inhibit B cell signal transduction through the recruitment of the SHPI and SHIP phosphatases. These observations provide insight into how CD19 governs the molecular ordering and intensity of signals transduced in B cells, and how perturbations in CD19 expression or signaling function may contribute to autoimmunity.

Authors
Fujimoto, M; Poe, JC; Hasegawa, M; Tedder, TF
MLA Citation
Fujimoto, M, Poe, JC, Hasegawa, M, and Tedder, TF. "CD19 regulates intrinsic B lymphocyte signal transduction and activation through a novel mechanism of processive amplification." Immunol Res 22.2-3 (2000): 281-298. (Review)
PMID
11339363
Source
pubmed
Published In
Immunologic Research
Volume
22
Issue
2-3
Publish Date
2000
Start Page
281
End Page
298
DOI
10.1385/IR:22:2-3:281

Manipulation of CD22 signal transduction for the treatment of lymphoma.

Authors
Tuscano, JM; DeNardo, G; Wun, T; Tedder, TF; Kehrl, JH
MLA Citation
Tuscano, JM, DeNardo, G, Wun, T, Tedder, TF, and Kehrl, JH. "Manipulation of CD22 signal transduction for the treatment of lymphoma." BLOOD 94.10 (November 15, 1999): 93A-93A.
Source
wos-lite
Published In
Blood
Volume
94
Issue
10
Publish Date
1999
Start Page
93A
End Page
93A

L-selectin ligands expressed by human leukocytes are HECA-452 antibody-defined carbohydrate epitopes preferentially displayed by P-selectin glycoprotein ligand-1.

Leukocytes express L-selectin ligands critical for leukocyte-leukocyte interactions at sites of inflammation. The predominant leukocyte L-selectin ligand is P-selectin glycoprotein ligand-1 (PSGL-1), which displays appropriate sialyl Lewis x (sLex)-like carbohydrate determinants for L-selectin recognition. Among the sLex-like determinants expressed by human leukocytes is a unique carbohydrate epitope defined by the HECA-452 mAb. The HECA-452 Ag is a critical component of L-selectin ligands expressed by vascular endothelial cells. However, HECA-452 Ag expression on human leukocyte L-selectin ligands has not been assessed. In this study, the HECA-452 mAb blocked 88-99% of neutrophil rolling on, or attachment to, adherent cells expressing L-selectin in multiple experimental systems. A function-blocking anti-PSGL-1 mAb also inhibited L-selectin binding to neutrophils by 89-98%. In addition, the HECA-452 and anti-PSGL-1 mAbs blocked the majority of P-selectin binding to neutrophils. Western blot analysis revealed that PSGL-1 immunoprecipitated from neutrophils displayed HECA-452 mAb-reactive determinants and that PSGL-1 was the predominant scaffold for HECA-452 Ag display. Leukocyte L-selectin ligands also contained sulfated determinants since culturing ligand-bearing cells with NaClO3 abrogated L-selectin binding. Consistent with this, human neutrophils expressed mRNA encoding five different sulfotransferases associated with the generation of selectin ligands: CHST1, CHST2, CHST3, TPST1, and HEC-GlcNAc6ST. Therefore, the HECA-452-defined carbohydrate determinant displayed on PSGL-1 represented the predominant L-selectin and P-selectin ligand expressed by neutrophils.

Authors
Tu, L; Murphy, PG; Li, X; Tedder, TF
MLA Citation
Tu, L, Murphy, PG, Li, X, and Tedder, TF. "L-selectin ligands expressed by human leukocytes are HECA-452 antibody-defined carbohydrate epitopes preferentially displayed by P-selectin glycoprotein ligand-1." J Immunol 163.9 (November 1, 1999): 5070-5078.
PMID
10528213
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
163
Issue
9
Publish Date
1999
Start Page
5070
End Page
5078

CD22 cross-linking generates B-cell antigen receptor-independent signals that activate the JNK/SAPK signaling cascade.

CD22 is a B-cell-specific adhesion molecule that modulates BCR-mediated signal transduction. Ligation of human CD22 with monoclonal antibodies (MoAbs) that block the ligand binding site triggers rapid tyrosine phosphorylation of CD22 and primary B-cell proliferation. Because extracellular signal-regulated kinases (ERKs) couple upstream signaling pathways to gene activation and are activated by B-cell antigen receptor (BCR) signaling, we examined whether CD22 ligation also activated ERKs and/or modified BCR-induced ERK activation. Ligation of CD22 on either primary B cells or B-cell lines failed to significantly activate the mitogen activated protein kinase (MAPK) ERK-2, but did activate the stress-activated protein kinases (SAPKs; c-jun NH2-terminal kinases or JNKs). In contrast, BCR ligation resulted in ERK-2 activation without significant SAPK activation. Concurrent ligation of CD22 and BCR enhanced BCR-mediated ERK-2 activation without appreciably modulating CD22-induced SAPK activation. Consistent with its induction of SAPK activity, there was a marked increase in nuclear extracts of activator protein-1 (AP-1) and c-jun levels within 2 hours of exposure of primary B cells to the CD22 MoAb. Despite their differences in ERK activation, both CD22 and BCR ligation triggered several Burkitt lymphoma cell lines to undergo apoptosis, and the 2 stimuli together induced greater cell death than either signal alone. The pro-apoptotic effects were CD22-blocking MoAb-specific and dose-dependent. Examination of expression levels of Bcl-2 protoncogene family members (Bcl-2, Bcl-x(L), Mcl-1, and Bax) showed a downregulation of Bcl-x(L) and Mcl-1 after CD22 ligation. This study provides a plausible mechanism to explain how CD22 and BCR signaling can costimulate B-cell proliferation and induce apoptosis in Burkitt lymphoma cell lines.

Authors
Tuscano, JM; Riva, A; Toscano, SN; Tedder, TF; Kehrl, JH
MLA Citation
Tuscano, JM, Riva, A, Toscano, SN, Tedder, TF, and Kehrl, JH. "CD22 cross-linking generates B-cell antigen receptor-independent signals that activate the JNK/SAPK signaling cascade." Blood 94.4 (August 15, 1999): 1382-1392.
PMID
10438726
Source
pubmed
Published In
Blood
Volume
94
Issue
4
Publish Date
1999
Start Page
1382
End Page
1392

Leukocyte entry into sites of inflammation requires overlapping interactions between the L-selectin and ICAM-1 pathways.

Leukocyte interactions with vascular endothelium during inflammation depend on cascades of adhesion molecule engagement, particularly during selectin-mediated leukocyte rolling. Leukocyte rolling is also facilitated by members of the integrin and Ig families. Specifically, leukocyte rolling velocities during inflammation are significantly increased in ICAM-1-deficient mice, with ICAM-1 expression required for optimal P- and L-selectin-mediated rolling. Elimination of ICAM-1 expression in L-selectin-deficient mice significantly reduces leukocyte rolling. Whether disrupted leukocyte rolling in L-selectin and ICAM-1 double-deficient (L-selectin/ICAM-1-/-) mice affects leukocyte entry into sites of inflammation in vivo was assessed in the current study by using experimental models of inflammation; thioglycollate-induced peritonitis, chemokine-induced neutrophil migration to the skin, delayed-type hypersensitivity responses, rejection of allogeneic skin grafts, and septic shock. In many cases, the loss of both L-selectin and ICAM-1 expression dramatically reduced leukocyte migration into sites of inflammation beyond what was observed with loss of either receptor alone. In fact, the effects from loss of both L-selectin and ICAM-1 effectively eliminated multiple chronic inflammatory responses in L-selectin/ICAM-1-/- mice. By contrast, the combined loss of L-selectin and ICAM-1 expression had minimal effects on the generation of Ag-specific T cell responses or humoral immunity. Thus, members of the selectin and Ig families function synergistically to mediate optimal leukocyte rolling and entry into tissues, which is essential for the generation of effective inflammatory responses in vivo.

Authors
Steeber, DA; Tang, ML; Green, NE; Zhang, XQ; Sloane, JE; Tedder, TF
MLA Citation
Steeber, DA, Tang, ML, Green, NE, Zhang, XQ, Sloane, JE, and Tedder, TF. "Leukocyte entry into sites of inflammation requires overlapping interactions between the L-selectin and ICAM-1 pathways." J Immunol 163.4 (August 15, 1999): 2176-2186.
PMID
10438959
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
163
Issue
4
Publish Date
1999
Start Page
2176
End Page
2186

Modulation of B lymphocyte antigen receptor signal transduction by a CD19/CD22 regulatory loop.

CD19 and CD22 are B lymphocyte cell-surface molecules that positively and negatively regulate antigen receptor signal transduction, respectively. Biochemical studies with B cells from CD19-deficient and CD22-deficient mice indicated that these two regulatory molecules influenced each other's functions: CD22 expression negatively regulated CD19 tyrosine phosphorylation, while optimal CD22 function was dependent on CD19 expression. Functional CD19 and CD22 interactions were also assessed in vivo by generating CD19/CD22 double-deficient mice. Remarkably, the CD19 mutation was dominant to the CD22 mutation in most instances. B lymphocytes from CD19/CD22-deficient and CD19-deficient mice were functionally equivalent despite the negative influence normally provided by CD22 expression. These data collectively suggest that CD19 activates the CD22/SHP1 inhibitory pathway that then acts primarily on CD19.

Authors
Fujimoto, M; Bradney, AP; Poe, JC; Steeber, DA; Tedder, TF
MLA Citation
Fujimoto, M, Bradney, AP, Poe, JC, Steeber, DA, and Tedder, TF. "Modulation of B lymphocyte antigen receptor signal transduction by a CD19/CD22 regulatory loop." Immunity 11.2 (August 1999): 191-200.
PMID
10485654
Source
pubmed
Published In
Immunity
Volume
11
Issue
2
Publish Date
1999
Start Page
191
End Page
200

Elevated serum L-selectin levels and abnormal regulation of L-selectin expression on leukocytes in atopic dermatitis: soluble L-selectin levels indicate disease severity.

BACKGROUND: L-selectin mediates leukocyte rolling on endothelium at sites of inflammation, suggesting that L-selectin may be involved in the development of cutaneous lesions of atopic dermatitis (AD). After leukocyte activation, L-selectin is rapidly shed from the cell surface. OBJECTIVE: The purpose of this study was to assess leukocyte L-selectin expression and quantitate levels of serum soluble L-selectin (sL-selectin) in patients with AD. METHODS: Serum sL-selectin levels in patients with AD (n = 70), contact dermatitis (n = 18), and psoriasis (n = 23), as well as normal control subjects (n = 30), were examined by using an ELISA. The L-selectin expression on leukocytes in heparinized blood samples from patients with AD (n = 18) and normal control subjects (n = 10) was also examined by flow cytometry. RESULTS: Serum levels of sL-selectin in patients with AD were significantly higher than those found in normal control subjects. Furthermore, sL-selectin levels correlated positively with disease severity and total serum IgE levels in AD. The expression of L-selectin on B cells, monocytes, and neutrophils was significantly decreased in patients with AD compared with normal control subjects, although those on CD4(+) or CD8(+) T cells from patients with AD were similar to those from normal control subjects. CONCLUSION: Elevated sL-selectin levels and the abnormal expression of L-selectin on some leukocyte subsets in patients with AD may correlate with inflammation associated with AD. Furthermore, the level of sL-selectin may be a useful immunologic indicator for disease activity in AD.

Authors
Shimada, Y; Sato, S; Hasegawa, M; Tedder, TF; Takehara, K
MLA Citation
Shimada, Y, Sato, S, Hasegawa, M, Tedder, TF, and Takehara, K. "Elevated serum L-selectin levels and abnormal regulation of L-selectin expression on leukocytes in atopic dermatitis: soluble L-selectin levels indicate disease severity." J Allergy Clin Immunol 104.1 (July 1999): 163-168.
PMID
10400854
Source
pubmed
Published In
Journal of Allergy and Clinical Immunology
Volume
104
Issue
1
Publish Date
1999
Start Page
163
End Page
168

CD19 amplifies B lymphocyte signal transduction by regulating Src-family protein tyrosine kinase activation.

Ligation of the B cell Ag receptor (BCR) induces cellular activation by stimulating Src-family protein tyrosine kinases (PTKs) to phosphorylate members of the BCR complex. Subsequently, Src-family PTKs, particularly Lyn, are proposed to phosphorylate and bind CD19, a cell-surface costimulatory molecule that regulates mature B cell activation. Herein, we show that B cells from CD19-deficient mice have diminished Lyn kinase activity and BCR phosphorylation following BCR ligation. Tyrosine phosphorylation of other Src-family PTKs was also decreased in CD19-deficient B cells. In wild-type B cells, CD19 was constitutively complexed with Vav, Lyn, and other Src-family PTKs, with CD19 phosphorylation and its associations with Lyn and Vav increased after BCR ligation. Constitutive CD19/Lyn/Vav complex signaling may therefore be responsible for the establishment of baseline signaling thresholds in B cells before Ag receptor ligation, in addition to accelerating signaling following BCR engagement or other transmembrane signals. In vitro kinase assays using purified CD19 and purified Lyn revealed that the kinase activity of Lyn was significantly increased when coincubated with CD19. Thus, constitutive and induced CD19/Lyn complexes are likely to regulate basal signaling thresholds and BCR signaling by amplifying the kinase activity of Lyn and other Src-family PTKs. These in vivo and in vitro findings demonstrate a novel mechanism by which CD19 regulates signal transduction in B lymphocytes. The absence of this CD19/Src-family kinase amplification loop may account for the hyporesponsive phenotype of CD19-deficient B cells.

Authors
Fujimoto, M; Poe, JC; Jansen, PJ; Sato, S; Tedder, TF
MLA Citation
Fujimoto, M, Poe, JC, Jansen, PJ, Sato, S, and Tedder, TF. "CD19 amplifies B lymphocyte signal transduction by regulating Src-family protein tyrosine kinase activation." J Immunol 162.12 (June 15, 1999): 7088-7094.
PMID
10358152
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
162
Issue
12
Publish Date
1999
Start Page
7088
End Page
7094

P-Selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver.

Hepatic damage following ischemia-reperfusion injury involves polymorphonuclear leukocytes (PMN) and platelet sequestration, however the mechanisms of adhesion remain elusive. In this study, using gene-targeted deficient mice, we evaluated P-selectin and its contribution to PMN and platelet adhesion in hepatic damage. In an in vivo warm ischemia model, hepatic injury was assessed by serum transaminase levels, survival, PMN adhesion by histological analysis, and platelet sequestration by immunostaining. Serum transaminase levels were strikingly reduced (by up to threefold) in the P-selectin deficient mice, particularly at 90 minutes of ischemia, when compared with wild-type controls. PMN adhesion and platelet sequestration was also significantly decreased in P-selectin deficient mice following 90 minutes of partial ischemia. Animal survival was significantly improved after 75 minutes of total hepatic ischemia in P-selectin deficient mice when compared with wild-type mice. Survival was also achieved after 90 minutes of ischemia in the mutant mice whereas none of the wild-type animals survived. These data show that P-selectin plays a critical role in PMN and platelet adhesion following ischemia-reperfusion injury to the liver.

Authors
Yadav, SS; Howell, DN; Steeber, DA; Harland, RC; Tedder, TF; Clavien, PA
MLA Citation
Yadav, SS, Howell, DN, Steeber, DA, Harland, RC, Tedder, TF, and Clavien, PA. "P-Selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver." Hepatology 29.5 (May 1999): 1494-1502.
PMID
10216134
Source
pubmed
Published In
Hepatology
Volume
29
Issue
5
Publish Date
1999
Start Page
1494
End Page
1502
DOI
10.1002/hep.510290505

CD19 expression regulates Src-family protein tyrosine kinase activation and Vav phosphorylation following B cell antigen receptor ligation

Authors
Fujimoto, M; Poe, JC; Jansen, PJ; Sato, S; Tedder, TF
MLA Citation
Fujimoto, M, Poe, JC, Jansen, PJ, Sato, S, and Tedder, TF. "CD19 expression regulates Src-family protein tyrosine kinase activation and Vav phosphorylation following B cell antigen receptor ligation." FASEB JOURNAL 13.5 (March 15, 1999): A988-A988.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
13
Issue
5
Publish Date
1999
Start Page
A988
End Page
A988

CD19 regulates CD22 function in B cell development and B cell antigen receptor signal transduction

Authors
Bradney, AP; Fujimoto, M; Poe, JC; Tedder, TF
MLA Citation
Bradney, AP, Fujimoto, M, Poe, JC, and Tedder, TF. "CD19 regulates CD22 function in B cell development and B cell antigen receptor signal transduction." FASEB JOURNAL 13.5 (March 15, 1999): A987-A987.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
13
Issue
5
Publish Date
1999
Start Page
A987
End Page
A987

The levels of CD19 expression on B lymphocytes regulate autoimmunity in patients with systemic sclerosis.

Authors
Sato, S; Hasegawa, M; Tedder, TF; Takehara, K
MLA Citation
Sato, S, Hasegawa, M, Tedder, TF, and Takehara, K. "The levels of CD19 expression on B lymphocytes regulate autoimmunity in patients with systemic sclerosis." FASEB JOURNAL 13.5 (March 15, 1999): A959-A959.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
13
Issue
5
Publish Date
1999
Start Page
A959
End Page
A959

CHST1 and CHST2: cDNA cloning of two sulfotransferases that may generate human vascular L-selectin ligands

Authors
Li, X; Tedder, TF
MLA Citation
Li, X, and Tedder, TF. "CHST1 and CHST2: cDNA cloning of two sulfotransferases that may generate human vascular L-selectin ligands." FASEB JOURNAL 13.4 (March 12, 1999): A314-A314.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
13
Issue
4
Publish Date
1999
Start Page
A314
End Page
A314

Induction of an important epitope on leukocyte L-selectin by mAb and hyperthermic conditions, and regulation by cytochalasin B.

Authors
Leid, JG; Steeber, DA; Tedder, TF; Jutila, MA
MLA Citation
Leid, JG, Steeber, DA, Tedder, TF, and Jutila, MA. "Induction of an important epitope on leukocyte L-selectin by mAb and hyperthermic conditions, and regulation by cytochalasin B." FASEB JOURNAL 13.4 (March 12, 1999): A313-A313.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
13
Issue
4
Publish Date
1999
Start Page
A313
End Page
A313

The cutaneous lymphocyte antigen (CLA) is an essential component of the L-selectin ligand induced on human vascular endothelial cells

Authors
Tu, LL; Delahunty, MD; Ding, H; Luscinskas, FW; Tedder, TF
MLA Citation
Tu, LL, Delahunty, MD, Ding, H, Luscinskas, FW, and Tedder, TF. "The cutaneous lymphocyte antigen (CLA) is an essential component of the L-selectin ligand induced on human vascular endothelial cells." FASEB JOURNAL 13.4 (March 12, 1999): A314-A314.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
13
Issue
4
Publish Date
1999
Start Page
A314
End Page
A314

L-selectin and beta 7 integrins synergistically regulate lymphocyte subset migration into lymphoid tissues

Authors
Steeber, DA; Zhang, XO; Wagner, N; Tedder, TF
MLA Citation
Steeber, DA, Zhang, XO, Wagner, N, and Tedder, TF. "L-selectin and beta 7 integrins synergistically regulate lymphocyte subset migration into lymphoid tissues." FASEB JOURNAL 13.4 (March 12, 1999): A313-A313.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
13
Issue
4
Publish Date
1999
Start Page
A313
End Page
A313

Overlapping roles for L-selectin and P-selectin in antigen-induced immune responses in the microvasculature.

Although L-selectin mediates lymphocyte attachment to endothelial venules of peripheral lymph nodes, its role in leukocyte recruitment into tissues following Ag challenge is less well established. The objective of this study was to systematically examine the role of L-selectin in leukocyte rolling in the peripheral microvasculature during the first 24 h of an immune response. A type I hypersensitivity response was elicited in wild-type (C57BL/6) and L-selectin-deficient mice by systemic (i.p.) sensitization and intrascrotal challenge with chicken egg OVA. The cremaster microcirculation was observed in untreated and sensitized mice 4, 8, and 24 h post-Ag challenge by intravital microscopy. Leukocyte recruitment in L-selectin-deficient mice and wild-type mice treated with an L-selectin function-blocking mAb was examined at each time point. Ag challenge induced a significant increase in leukocyte rolling (60 cells/min/venule to approximately 300 cells/min/venule) in wild-type mice at 4-24 h. This response was reduced by approximately 60-70% in L-selectin-deficient mice and in wild-type mice treated with an L-selectin-blocking mAb. P-selectin blockade by Ab completely inhibited leukocyte rolling at 4-24 h in wild-type animals and also blocked the residual rolling seen in L-selectin-deficient mice. Blocking E-selectin function had no effect on leukocyte rolling flux at any time point in wild-type or L-selectin-deficient mice. Despite reduced rolling, leukocyte adhesion and emigration were not measurably reduced in the L-selectin-deficient mice in this vascular bed. In conclusion, leukocyte rolling is L-selectin-dependent post-Ag challenge with L-selectin and P-selectin sharing overlapping functions.

Authors
Kanwar, S; Steeber, DA; Tedder, TF; Hickey, MJ; Kubes, P
MLA Citation
Kanwar, S, Steeber, DA, Tedder, TF, Hickey, MJ, and Kubes, P. "Overlapping roles for L-selectin and P-selectin in antigen-induced immune responses in the microvasculature." J Immunol 162.5 (March 1, 1999): 2709-2716.
PMID
10072515
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
162
Issue
5
Publish Date
1999
Start Page
2709
End Page
2716

CD1 expression by dendritic cells in human leprosy lesions: correlation with effective host immunity.

A potential role for the CD1 family of lipid Ag-presenting molecules in antimicrobial immunity in vivo was investigated in human leprosy skin lesions. Strong induction of three CD1 proteins (CD1a, -b, and -c) was observed in dermal granulomas in biopsy samples of involved skin from patients with the tuberculoid form of leprosy or with reversal reactions, which represent clinical patterns of disease associated with active cellular immunity to Mycobacterium leprae. In contrast, lesions from patients with the lepromatous form of the disease who lack effective cell-mediated immunity to the pathogen did not show induction of CD1 proteins. Thus, expression of CD1 correlated directly with effective immunity to M. leprae, as assessed by the clinical course of infection. CD1a, -b, and -c could be induced to similar levels on monocytes from the blood of either tuberculoid or lepromatous leprosy patients. This suggested that the absence of expression in lepromatous lesions was most likely due to local factors at the site of infection as opposed to a primary defect of the CD1 system itself. The majority of cells expressing CD1 in leprosy lesions were identified as a population of CD83+ dendritic cells. Initial in vitro studies of the Ag-presenting function of CD1+CD83+ monocyte-derived dendritic cells showed that such cells were highly efficient APCs for CD1-restricted T cells. These results indicate that the CD1 system can be up-regulated in human infectious diseases in vivo, and may play a role in augmenting host defense against microbial pathogens.

Authors
Sieling, PA; Jullien, D; Dahlem, M; Tedder, TF; Rea, TH; Modlin, RL; Porcelli, SA
MLA Citation
Sieling, PA, Jullien, D, Dahlem, M, Tedder, TF, Rea, TH, Modlin, RL, and Porcelli, SA. "CD1 expression by dendritic cells in human leprosy lesions: correlation with effective host immunity." J Immunol 162.3 (February 1, 1999): 1851-1858.
PMID
9973451
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
162
Issue
3
Publish Date
1999
Start Page
1851
End Page
1858

CHST1 and CHST2 sulfotransferases expressed by human vascular endothelial cells: cDNA cloning, expression, and chromosomal localization.

Sulfation is essential for the generation of functional vascular endothelial cell ligands for the leukocyte adhesion molecule, L-selectin. Therefore, human vascular endothelium cDNA libraries were screened to identify sulfotransferases homologous to chicken chondroitin 6-sulfotransferase (C6ST). Two sulfotransferases were identified: CHST2, a novel 530-amino-acid sulfotransferase with a carboxyl-terminal region that was 45 and 43% homologous with those of human and chicken C6ST, respectively, and CHST1, which was identical to human C6ST. Northern blot analysis showed that CHST2 was broadly expressed among tissues. The CHST2 gene mapped to human chromosome 3q24 close to 3q25. Thus, this study identified two sulfotransferases expressed by vascular endothelial cells that may contribute to the generation of L-selectin ligands during inflammatory responses.

Authors
Li, X; Tedder, TF
MLA Citation
Li, X, and Tedder, TF. "CHST1 and CHST2 sulfotransferases expressed by human vascular endothelial cells: cDNA cloning, expression, and chromosomal localization." Genomics 55.3 (February 1, 1999): 345-347.
PMID
10049591
Source
pubmed
Published In
Genomics
Volume
55
Issue
3
Publish Date
1999
Start Page
345
End Page
347
DOI
10.1006/geno.1998.5653

The cutaneous lymphocyte antigen is an essential component of the L-selectin ligand induced on human vascular endothelial cells.

L-selectin mediates leukocyte rolling on vascular endothelium during inflammation. Although vascular endothelium can be activated with inflammatory cytokines to express functional L-selectin ligands, these ligands have not been well characterized. In this study, fucosyltransferase VII cDNA (Fuc-TVII) transfection of the EA.hy926 human vascular endothelial cell line (926-FtVII) induced functional L-selectin ligand expression and expression of sialyl Lewisx (sLex), as defined by HECA-452 (cutaneous lymphocyte antigen; CLA) and CSLEX-1 mAbs. Cytokine activation of human umbilical vein endothelial cells (HUVEC) also induced functional L-selectin ligand expression, with increased CLA expression and Fuc-TVII transcription. The majority of L-selectin-dependent lymphocyte attachment to activated HUVEC and 926-FtVII cells was blocked specifically by treating the endothelial cells with the HECA-452 mAb, but not the CSLEX-1 mAb. CLA-bearing ligands on vascular endothelium also required sulfation and appropriate molecular scaffolds for functional activity, but were distinct from the L-selectin ligands previously identified by the MECA-79 mAb. These findings demonstrate that the HECA-452- defined antigen, CLA, is an essential carbohydrate component of vascular L-selectin ligands.

Authors
Tu, L; Delahunty, MD; Ding, H; Luscinskas, FW; Tedder, TF
MLA Citation
Tu, L, Delahunty, MD, Ding, H, Luscinskas, FW, and Tedder, TF. "The cutaneous lymphocyte antigen is an essential component of the L-selectin ligand induced on human vascular endothelial cells." J Exp Med 189.2 (January 18, 1999): 241-252.
PMID
9892607
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
189
Issue
2
Publish Date
1999
Start Page
241
End Page
252

The Selectins and their Ligands. Adhesion Molecules of the Vasculature

Authors
Tedder, TF; Li, X; Steeber, DA
MLA Citation
Tedder, TF, Li, X, and Steeber, DA. "The Selectins and their Ligands. Adhesion Molecules of the Vasculature." Advances in Molecular and Cell Biology 28.C (1999): 65-111.
Source
scival
Published In
Advances in Molecular and Cell Biology
Volume
28
Issue
C
Publish Date
1999
Start Page
65
End Page
111
DOI
10.1016/S1569-2558(08)60044-2

Efficient lymphocyte migration across high endothelial venules of mouse Peyer's patches requires overlapping expression of L-selectin and beta7 integrin.

Lymphocyte migration into lymphoid organs is regulated by adhesion molecules including L-selectin and the beta7 integrins. L-selectin and alpha4beta7 are predominantly hypothesized to direct the selective migration of lymphocytes to peripheral lymph nodes and the gut-associated lymphoid tissues, respectively. To further characterize interactions between L-selectin and beta7 integrins during lymphocyte recirculation, mice deficient in both receptors (L-selectin/beta7 integrin-/-) were generated. The simultaneous loss of L-selectin and beta7 integrin expression prevented the majority of lymphocytes (>95% inhibition) from attaching to high endothelial venules (HEV) of Peyer's patches and other lymphoid tissues during in vitro binding assays. Moreover, the inability to bind HEV eliminated the vast majority of L-selectin/beta7 integrin-/- lymphocyte migration into Peyer's patches during short-term and long-term in vivo migration assays (>99% inhibition,p < 0.01). The lack of lymphocyte migration into Peyer's patches correlated directly with the dramatically reduced size and cellularity (99% reduced) of this tissue in L-selectin/beta7 integrin-/- mice. High numbers of injected L-selectin/beta7 integrin-/- lymphocytes remaining in the blood of wild-type mice correlated with markedly increased numbers of circulating lymphocytes in L-selectin/beta7 integrin-/- mice. Loss of either L-selectin or the beta7 integrins alone resulted in significant but incomplete inhibition of Peyer's patch migration. Collectively, the phenotype of L-selectin/beta7 integrin-/- mice demonstrates that these two receptors primarily interact along the same adhesion pathway that is required for the vast majority of lymphocyte migration into Peyer's patches.

Authors
Steeber, DA; Tang, ML; Zhang, XQ; Müller, W; Wagner, N; Tedder, TF
MLA Citation
Steeber, DA, Tang, ML, Zhang, XQ, Müller, W, Wagner, N, and Tedder, TF. "Efficient lymphocyte migration across high endothelial venules of mouse Peyer's patches requires overlapping expression of L-selectin and beta7 integrin." J Immunol 161.12 (December 15, 1998): 6638-6647.
PMID
9862692
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
161
Issue
12
Publish Date
1998
Start Page
6638
End Page
6647

The role of adhesion molecules in human leukocyte attachment to porcine vascular endothelium: implications for xenotransplantation.

Many obstacles still prevent successful xenotransplantation of porcine donor organs. When hyperacute rejection is averted, transplanted pig organs are subject to acute vascular and cellular rejection. In autologous systems, leukocyte recruitment into inflamed tissues involves selectins, integrins, and Ig family members. To determine whether these mechanisms allow human leukocytes to effectively enter porcine grafts, the pathways by which human leukocytes adhere to TNF-alpha-stimulated porcine aortic endothelium were examined under static and physiologic flow conditions. L-selectin and E-selectin had overlapping functions in neutrophil capture and rolling, whereas Ab blockade of E-selectin and the beta2 integrins inhibited firm arrest of rolling neutrophils. Combined blockade of selectins and beta2 integrins resulted in negligible human neutrophil attachment to pig endothelium. Lymphocyte attachment to porcine endothelium was primarily L-selectin mediated, whereas beta2 integrin and VCAM-1/very late Ag-4 (VLA-4) interactions promoted static adhesion. Concurrent beta2 integrin, VLA-4, VCAM-1, and L-selectin blockade completely inhibited lymphocyte attachment. Thus, interactions between leukocyte-endothelial cell adhesion receptor pairs remained remarkably intact across the human-porcine species barrier. Moreover, disrupting the adhesion cascade may impair the ability of human leukocytes to infiltrate a transplanted porcine organ during rejection.

Authors
Robinson, LA; Tu, L; Steeber, DA; Preis, O; Platt, JL; Tedder, TF
MLA Citation
Robinson, LA, Tu, L, Steeber, DA, Preis, O, Platt, JL, and Tedder, TF. "The role of adhesion molecules in human leukocyte attachment to porcine vascular endothelium: implications for xenotransplantation." J Immunol 161.12 (December 15, 1998): 6931-6938.
PMID
9862727
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
161
Issue
12
Publish Date
1998
Start Page
6931
End Page
6938

The mouse Cd83 gene: structure, domain organization, and chromosome localization.

Human CD83 (hCD83) is a 45 000 Mr cell-surface protein expressed predominantly by dendritic lineage cells. In this report, the genomic locus encoding mouse CD83 (Cd83) was isolated and the gene structure determined. The Cd83 gene spans approximately 19 kilobases (kb) and is composed of five exons, with two exons encoding a single extracellular immunoglobulin (Ig)-like domain. Mouse CD83 (mCD83) cDNAs were isolated by reverse transcriptase polymerase chain reaction of mouse RNA. Sequence determination revealed substantial conservation, with mCD83 and hCD83 sharing 63% amino acid identity. The transmembrane and cytoplasmic regions of CD83 were most highly conserved. Mouse CD83 mRNA of 2.4 kb was abundantly expressed in spleen and brain, but could also be detected in most tissues analyzed. These results suggest that in the mouse, as in humans, widely distributed dendritic cells may express mCD83. Chromosome localization revealed that the Cd83 gene is present on mouse chromosome 13 band A5, while the locus for the human gene (CD83) is located within a homologous region of human chromosome 6p23. Thus, the CD83 protein and gene appear to be well conserved during recent mammalian evolution. The isolation and characterization of the mCD83 cDNA and gene provides important information and tools that will facilitate the study of CD83 and dendritic cell function in a mouse model system.

Authors
Twist, CJ; Beier, DR; Disteche, CM; Edelhoff, S; Tedder, TF
MLA Citation
Twist, CJ, Beier, DR, Disteche, CM, Edelhoff, S, and Tedder, TF. "The mouse Cd83 gene: structure, domain organization, and chromosome localization." Immunogenetics 48.6 (November 1998): 383-393.
PMID
9799334
Source
pubmed
Published In
Immunogenetics
Volume
48
Issue
6
Publish Date
1998
Start Page
383
End Page
393

L-selectin and beta7 integrin synergistically mediate lymphocyte migration to mesenteric lymph nodes.

Mesenteric lymph nodes (MLN) drain the gut where nutritive antigens and pathogens are encountered by lymphocytes of the gut-associated lymphoid tissue. We sought to determine how lymphocytes enter the MLN by studying mice double deficient for beta7 integrins and L-selectin. beta7/L-selectin double-deficient lymphocytes did not migrate into MLN. Most importantly, MLN formation was drastically impaired in beta7/L-selectin double-deficient mice. Lymphocyte numbers in MLN from beta7/L-selectin double-deficient mice were tenfold reduced compared to control mice. A high percentage of the few lymphocytes still detected in MLN from beta7/L-selectin double-deficient mice were CD44hi CD18hi, suggesting alternate migration pathways independent of L-selectin and beta7 integrin for these cells. We conclude that the combination of both molecules, L-selectin and beta7 integrin, is indispensable for MLN formation and that these molecules may mediate lymphocyte migration to MLN in a sequential and synergistical manner.

Authors
Wagner, N; Löhler, J; Tedder, TF; Rajewsky, K; Müller, W; Steeber, DA
MLA Citation
Wagner, N, Löhler, J, Tedder, TF, Rajewsky, K, Müller, W, and Steeber, DA. "L-selectin and beta7 integrin synergistically mediate lymphocyte migration to mesenteric lymph nodes." Eur J Immunol 28.11 (November 1998): 3832-3839.
PMID
9842926
Source
pubmed
Published In
European Journal of Immunology
Volume
28
Issue
11
Publish Date
1998
Start Page
3832
End Page
3839

Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow.

Leukocyte migration into sites of inflammation involves multiple molecular interactions between leukocytes and vascular endothelial cells, mediating sequential leukocyte capture, rolling, and firm adhesion. In this study, we tested the role of molecular interactions between fractalkine (FKN), a transmembrane mucin-chemokine hybrid molecule expressed on activated endothelium, and its receptor (CX3CR1) in leukocyte capture, firm adhesion, and activation under physiologic flow conditions. Immobilized FKN fusion proteins captured resting peripheral blood mononuclear cells at physiologic wall shear stresses and induced firm adhesion of resting monocytes, resting and interleukin (IL)-2-activated CD8(+) T lymphocytes and IL-2-activated NK cells. FKN also induced cell shape change in firmly adherent monocytes and IL-2-activated lymphocytes. CX3CR1-transfected K562 cells, but not control K562 cells, firmly adhered to FKN-expressing ECV-304 cells (ECV-FKN) and tumor necrosis factor alpha-activated human umbilical vein endothelial cells. This firm adhesion was not inhibited by pertussis toxin, EDTA/EGTA, or antiintegrin antibodies, indicating that the firm adhesion was integrin independent. In summary, FKN mediated the rapid capture, integrin-independent firm adhesion, and activation of circulating leukocytes under flow. Thus, FKN and CX3CR1 mediate a novel pathway for leukocyte trafficking.

Authors
Fong, AM; Robinson, LA; Steeber, DA; Tedder, TF; Yoshie, O; Imai, T; Patel, DD
MLA Citation
Fong, AM, Robinson, LA, Steeber, DA, Tedder, TF, Yoshie, O, Imai, T, and Patel, DD. "Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow." J Exp Med 188.8 (October 19, 1998): 1413-1419.
PMID
9782118
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
188
Issue
8
Publish Date
1998
Start Page
1413
End Page
1419

Regulation of L-selectin-mediated rolling through receptor dimerization.

L-selectin binding activity for its ligand expressed by vascular endothelium is rapidly and transiently increased after leukocyte activation. To identify mechanisms for upregulation and assess how this influences leukocyte/endothelial cell interactions, cell-surface dimers of L-selectin were induced using the coumermycin-GyrB dimerization strategy for cross-linking L-selectin cytoplasmic domains in L-selectin cDNA-transfected lymphoblastoid cells. Coumermycin- induced L-selectin dimerization resulted in an approximately fourfold increase in binding of phosphomanan monoester core complex (PPME), a natural mimic of an L-selectin ligand, comparable to that observed after leukocyte activation. Moreover, L-selectin dimerization significantly increased (by approximately 700%) the number of lymphocytes rolling on vascular endothelium under a broad range of physiological shear stresses, and significantly slowed their rolling velocities. Therefore, L-selectin dimerization may explain the rapid increase in ligand binding activity that occurs after leukocyte activation and may directly influence leukocyte migration to peripheral lymphoid tissues or to sites of inflammation. Inducible oligomerization may also be a common mechanism for rapidly upregulating the adhesive or ligand-binding function of other cell-surface receptors.

Authors
Li, X; Steeber, DA; Tang, ML; Farrar, MA; Perlmutter, RM; Tedder, TF
MLA Citation
Li, X, Steeber, DA, Tang, ML, Farrar, MA, Perlmutter, RM, and Tedder, TF. "Regulation of L-selectin-mediated rolling through receptor dimerization." J Exp Med 188.7 (October 5, 1998): 1385-1390.
PMID
9763619
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
188
Issue
7
Publish Date
1998
Start Page
1385
End Page
1390

The roles of L-selectin, beta 7 integrins, and P-selectin in leukocyte rolling and adhesion in high endothelial venules of Peyer's patches.

Lymphocyte trafficking into Peyer's patches requires beta 7 integrins and L-selectin. Here, we use intravital microscopy to examine leukocyte rolling and adhesion in Peyer's patch high endothelial venules (HEV) of wild-type, L-selectin-deficient (L-/-), beta 7 integrin-deficient (beta 7-/-), and beta 7/L(-/-) mice. Although the leukocyte rolling flux fraction was reduced by 70%, Peyer's patches in L-/- mice were of normal size and cellularity. In beta 7-/- mice, the rolling flux fraction was normal, but the number of adherent leukocytes in HEV was greatly reduced. The median leukocyte rolling velocity was reduced in L-/- mice and increased in beta 7-/- mice, suggesting that beta 7 integrins and L-selectin mediate rolling in Peyer's patch HEV at different velocities. beta 7/L(-/-) exhibited both a low rolling flux fraction and low adhesion and had severely reduced Peyer's patch size and cellularity. The residual rolling in these mice was completely blocked by a P-selectin mAb. A significant P-selectin component was also detected in the other genotypes. Twenty-six percent of B and T lymphocytes isolated from Peyer's patches of wild-type mice expressed functional ligands for P-selectin, and this fraction was increased to 57% in beta 7/L(-/-) mice. Peyer's patch HEV were found to express P-selectin under the conditions of intravital microscopy, but not in situ. Our data suggest a novel P-selectin dependent mechanism of lymphocyte homing to Peyer's patches. In situ, beta 7 integrins and L-selectin account for all lymphocyte homing to Peyer's patches, but P-selectin-dependent rolling, as induced by minimal trauma, may support trafficking of effector T lymphocytes to Peyer's patches.

Authors
Kunkel, EJ; Ramos, CL; Steeber, DA; Müller, W; Wagner, N; Tedder, TF; Ley, K
MLA Citation
Kunkel, EJ, Ramos, CL, Steeber, DA, Müller, W, Wagner, N, Tedder, TF, and Ley, K. "The roles of L-selectin, beta 7 integrins, and P-selectin in leukocyte rolling and adhesion in high endothelial venules of Peyer's patches." J Immunol 161.5 (September 1, 1998): 2449-2456.
PMID
9725243
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
161
Issue
5
Publish Date
1998
Start Page
2449
End Page
2456

Introduction: response-regulators of B lymphocyte signaling thresholds provide a context for antigen receptor signal transduction.

Authors
Tedder, TF
MLA Citation
Tedder, TF. "Introduction: response-regulators of B lymphocyte signaling thresholds provide a context for antigen receptor signal transduction." Semin Immunol 10.4 (August 1998): 259-265.
PMID
9695182
Source
pubmed
Published In
Seminars in Immunology
Volume
10
Issue
4
Publish Date
1998
Start Page
259
End Page
265
DOI
10.1006/smim.1998.0118

CD22 negatively and positively regulates signal transduction through the B lymphocyte antigen receptor.

The CD22 cell-surface adhesion molecule is capable of modulating B lymphocyte antigen receptor (BCR)-mediated signals, as well as the generation of BCR-independent signals. Within the cytoplasmic domain of CD22 are motifs that are structurally homologous to known activation and inhibitory motifs. These motifs demonstrate physiologic significance via associations with known effector proteins that likely mediate their corresponding inhibitory and activation roles. Furthermore, the targeted deletion of CD22 in mice results in phenotypic changes and alterations in BCR-mediated signal transduction that are consistent with both positive and negative roles for CD22 in B cell development and activation.

Authors
Sato, S; Tuscano, JM; Inaoki, M; Tedder, TF
MLA Citation
Sato, S, Tuscano, JM, Inaoki, M, and Tedder, TF. "CD22 negatively and positively regulates signal transduction through the B lymphocyte antigen receptor." Semin Immunol 10.4 (August 1998): 287-297. (Review)
PMID
9695185
Source
pubmed
Published In
Seminars in Immunology
Volume
10
Issue
4
Publish Date
1998
Start Page
287
End Page
297
DOI
10.1006/smim.1998.0121

CD19 regulates B lymphocyte responses to transmembrane signals.

CD19 is a component of a cell surface receptor complex that regulates B lymphocyte responses to transmembrane signals including those generated through the B cell antigen receptor. Studies in mice which lack or overexpress CD19 show that changes in CD19 expression levels have significant effects on B cell development and function. Recent studies suggest that CD19 establishes a Src-family kinase activation loop that amplifies tyrosine phosphorylation of numerous downstream effector molecules including potentially positive and negative regulatory elements. These observations provide an understanding of how CD19 governs the molecular ordering and intensity of signals transduced through multiple B cell receptors.

Authors
Fujimoto, M; Poe, JC; Inaoki, M; Tedder, TF
MLA Citation
Fujimoto, M, Poe, JC, Inaoki, M, and Tedder, TF. "CD19 regulates B lymphocyte responses to transmembrane signals." Semin Immunol 10.4 (August 1998): 267-277. (Review)
PMID
9695183
Source
pubmed
Published In
Seminars in Immunology
Volume
10
Issue
4
Publish Date
1998
Start Page
267
End Page
277
DOI
10.1006/smim.1998.9999

Optimal selectin-mediated rolling of leukocytes during inflammation in vivo requires intercellular adhesion molecule-1 expression.

Leukocyte interactions with vascular endothelium during inflammation occur through discrete steps involving selectin-mediated leukocyte rolling and subsequent firm adhesion mediated by members of the integrin and Ig families of adhesion molecules. To identify functional synergy between selectin and Ig family members, mice deficient in both L-selectin and intercellular adhesion molecule 1 (ICAM-1) were generated. Leukocyte rolling velocities in cremaster muscle venules were increased significantly in ICAM-1-deficient mice during both trauma- and tumor necrosis factor alpha-induced inflammation, but rolling leukocyte flux was not reduced. Elimination of ICAM-1 expression in L-selectin-deficient mice resulted in a sharp reduction in the flux of rolling leukocytes during tumor necrosis factor alpha-induced inflammation. The observed differences in leukocyte rolling behavior demonstrated that ICAM-1 expression was required for optimal P- and L-selectin-mediated rolling. Increased leukocyte rolling velocities presumably translated into decreased tissue emigration because circulating neutrophil, monocyte, and lymphocyte numbers were increased markedly in L-selectin/ICAM-1-deficient mice. Furthermore, neutrophil emigration during acute peritonitis was reduced by 80% in the double-deficient mice compared with either L-selectin or ICAM-1-deficient mice. Thus, members of the selectin and Ig families function synergistically to mediate optimal leukocyte rolling in vivo, which is essential for the generation of effective inflammatory responses.

Authors
Steeber, DA; Campbell, MA; Basit, A; Ley, K; Tedder, TF
MLA Citation
Steeber, DA, Campbell, MA, Basit, A, Ley, K, and Tedder, TF. "Optimal selectin-mediated rolling of leukocytes during inflammation in vivo requires intercellular adhesion molecule-1 expression." Proc Natl Acad Sci U S A 95.13 (June 23, 1998): 7562-7567.
PMID
9636189
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
95
Issue
13
Publish Date
1998
Start Page
7562
End Page
7567

Intrinsic differences in L-selectin expression levels affect T and B lymphocyte subset-specific recirculation pathways.

Lymphocyte migration into lymphoid organs is regulated by tissue-specific adhesion molecules such as L-selectin and the alpha4beta7 integrin. Whether L-selectin also regulates lymphocyte subset-specific migration into specific lymphoid tissues was examined in this study by comparing the migration of CD4+ T cells, CD8+ T cells, and B cells from L-selectin-deficient and wild-type mice. T cells were the predominant lymphocyte subset entering PLN, MLN, Peyer's patches, and spleen during short term (1-h) migration assays. However, both B cell and CD4+ and CD8+ T cell entries into PLN, MLN, and Peyer's patches were dramatically impaired (73-98%) by loss of L-selectin. Lymphocyte expression of alpha4beta7 integrin did not compensate for the loss of L-selectin, since both B and T cells predominantly migrated into the spleen in the absence of L-selectin. The more efficient migration of T cells into peripheral lymphoid tissues relative to that of B cells was partly explained by the finding that T cells expressed L-selectin at 50 to 100% higher levels than B cells. In addition, a 50% reduction in L-selectin expression by lymphocytes from hemizygous L-selectin(+/-) mice resulted in a 50 to 70% decrease in short term lymphocyte migration into peripheral lymphoid tissues relative to that of wild-type lymphocytes. Thus, the differential migration of T and B lymphocyte subsets to lymphoid tissues is regulated in part by subset-specific differences in L-selectin expression levels.

Authors
Tang, ML; Steeber, DA; Zhang, XQ; Tedder, TF
MLA Citation
Tang, ML, Steeber, DA, Zhang, XQ, and Tedder, TF. "Intrinsic differences in L-selectin expression levels affect T and B lymphocyte subset-specific recirculation pathways." J Immunol 160.10 (May 15, 1998): 5113-5121.
PMID
9590263
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
160
Issue
10
Publish Date
1998
Start Page
5113
End Page
5121

A novel mechanism for leukocyte migration: Fractalkine mediates the rapid capture and integrin-independent firm adhesion of circulating leukocytes.

Authors
Patel, DD; Fong, AM; Robinson, LA; Steeber, DA; Tedder, TF; Yoshie, O; Imai, T
MLA Citation
Patel, DD, Fong, AM, Robinson, LA, Steeber, DA, Tedder, TF, Yoshie, O, and Imai, T. "A novel mechanism for leukocyte migration: Fractalkine mediates the rapid capture and integrin-independent firm adhesion of circulating leukocytes." JOURNAL OF INVESTIGATIVE MEDICINE 46.3 (March 1998): 235A-235A.
Source
wos-lite
Published In
Journal of Investigative Medicine
Volume
46
Issue
3
Publish Date
1998
Start Page
235A
End Page
235A

CD antigens 1996: Updated nomenclature for clusters of differentiation on human cells

The 6th International Workshop on Human Leukocyte Differentiation Antigens, held in Kobe, Japan, on 1014 November 1996, recommended the adoption of 41 new CD clusters and subclusters and the redefinition of 20 previously established clusters. The additions and changes are summarized in tabular form in this article.

Authors
Turner, MW; Schlossman, SF; Boumsell, L; Kishimoto, T; Knapp, W; Mason, D; McMichael, A; Shaw, S; Springer, TA; Tedder, T; Todd, R; Waldman, H; Zola, H
MLA Citation
Turner, MW, Schlossman, SF, Boumsell, L, Kishimoto, T, Knapp, W, Mason, D, McMichael, A, Shaw, S, Springer, TA, Tedder, T, Todd, R, Waldman, H, and Zola, H. "CD antigens 1996: Updated nomenclature for clusters of differentiation on human cells." Immunologist 6.SUPPL. 2 (1998): 118--.
Source
scival
Published In
Immunologist
Volume
6
Issue
SUPPL. 2
Publish Date
1998
Start Page
118-

The role of L-selectin in leukocyte recruitment at various stages of an acute allergic response

The objective of this study was to systematically examine the role of L-selectin in leukocyte recruitment under baseline conditions and during allergic inflammation. A Type I hypersensitivity response was elicited in wild type (C57BI/6) and L-selectin-deficient mice by systemic (ip) sensitization and intrascrotal challenge with chicken ovalbumin. The cremasteric microcirculation was observed (intravital microscopy) in untreated animals (baseline), and at 4, 8 and 24 hrs post-antigen challenge in sensitized animals. Administration of an anti-L-selectin antibody, or deletion of L-selectin (L-selectin-deficient) had absolutely no affect on baseline leukocyte recruitment. Antigen challenge in wild type animals induced a significant increase in leukocyte rolling, adhesion and emigration at all time points examined. An anti-L-selectin antibody reduced antigen-induced leukocyte rolling by 60-70% at 4, 8 and 24 hrs post challenge. In addition, antigen-induced leukocyte rolling was reduced by 70% in L-selectin-deficient animals. Despite a reduction in rolling, however, antigen-induced leukocyte adhesion and emigration were not affected by either an anti-L-selectin antibody or L-selectin deletion. In conclusion, L-selectin does not play a role in leukocyte recruitment under baseline conditions. L-selectin contributes significantly to antigen-induced leukocyte rolling, however, overall leukocyte recruitment is not compromised.

Authors
Kubes, P; Steeber, DA; Tedder, TF; Kanwar, S
MLA Citation
Kubes, P, Steeber, DA, Tedder, TF, and Kanwar, S. "The role of L-selectin in leukocyte recruitment at various stages of an acute allergic response." FASEB Journal 12.5 (1998): A806-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
12
Issue
5
Publish Date
1998
Start Page
A806

CD antigens 1993: An updated nomenclature for clusters of differentiation on human cells

The 5th International Workshop on Human Leukocyte Differentiation Antigens (Boston, USA, 3-7 November 1993) recommended the adoption of 48 new CD clusters and subclusters and the redefinition of 14 previously established clusters. The additions and changes made to the existing CD nomenclature are summarized in a Table.

Authors
Kazatchkine, M; Schlossmann, SF; Boumsell, L; Gilks, W; Harian, JM; Kishimoto, T; Morimoto, C; Ritz, J; Shaw, S; Silverstein, RL; Springer, TA; Tedder, TF; Todd, RF
MLA Citation
Kazatchkine, M, Schlossmann, SF, Boumsell, L, Gilks, W, Harian, JM, Kishimoto, T, Morimoto, C, Ritz, J, Shaw, S, Silverstein, RL, Springer, TA, Tedder, TF, and Todd, RF. "CD antigens 1993: An updated nomenclature for clusters of differentiation on human cells." Immunologist 6.SUPPL. 2 (1998): 116--.
Source
scival
Published In
Immunologist
Volume
6
Issue
SUPPL. 2
Publish Date
1998
Start Page
116-

CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes.

The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.

Authors
Inaoki, M; Sato, S; Weintraub, BC; Goodnow, CC; Tedder, TF
MLA Citation
Inaoki, M, Sato, S, Weintraub, BC, Goodnow, CC, and Tedder, TF. "CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes." J Exp Med 186.11 (December 1, 1997): 1923-1931.
PMID
9382890
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
186
Issue
11
Publish Date
1997
Start Page
1923
End Page
1931

CD19 and CD22 expression reciprocally regulates tyrosine phosphorylation of Vav protein during B lymphocyte signaling.

B cell development and humoral immune responses are controlled by signaling thresholds established through the B lymphocyte antigen receptor (BCR) complex. BCR signaling thresholds are differentially regulated by the CD22 and CD19 cell surface receptors in vivo. B cells from CD22-deficient mice exhibit characteristics of chronic stimulation and are hyper-responsive to BCR crosslinking with augmented intracellular Ca2+ responses. By contrast, B cells from CD19-deficient mice are hypo-responsive to transmembrane signals. To identify signaling molecules involved in the positive and negative regulation of signaling thresholds, the signal transduction pathways activated after BCR crosslinking were examined in CD22- and CD19-deficient B cells. These comparisons revealed that tyrosine phosphorylation of Vav protein was uniquely augmented after BCR or CD19 crosslinking in CD22-deficient B cells, yet was modest and transient after BCR crosslinking in CD19-deficient B cells. Ligation of CD19 and CD22 in vivo is likely to positively and negatively regulate BCR signaling, respectively, because CD19 crosslinking was more efficient than BCR crosslinking at inducing Vav phosphorylation. However, simultaneous crosslinking of CD19 with the BCR resulted in a substantial decrease in Vav phosphorylation when CD22 was expressed. Thus, the differential regulation of Vav tyrosine phosphorylation by CD19 and CD22 may provide a molecular mechanism for adjusting BCR signaling thresholds.

Authors
Sato, S; Jansen, PJ; Tedder, TF
MLA Citation
Sato, S, Jansen, PJ, and Tedder, TF. "CD19 and CD22 expression reciprocally regulates tyrosine phosphorylation of Vav protein during B lymphocyte signaling." Proc Natl Acad Sci U S A 94.24 (November 25, 1997): 13158-13162.
PMID
9371816
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
94
Issue
24
Publish Date
1997
Start Page
13158
End Page
13162

Cloning, expression and characterization of recombinant PE38 immunotoxins directed against CD19 antigen for the therapy of B-cell malignancies

Authors
Nambiar, MP; Tedder, TF; Pastan, IH; FitzGerald, DJ
MLA Citation
Nambiar, MP, Tedder, TF, Pastan, IH, and FitzGerald, DJ. "Cloning, expression and characterization of recombinant PE38 immunotoxins directed against CD19 antigen for the therapy of B-cell malignancies." MOLECULAR BIOLOGY OF THE CELL 8 (November 1997): 1788-1788.
Source
wos-lite
Published In
Molecular Biology of the Cell
Volume
8
Publish Date
1997
Start Page
1788
End Page
1788

Regulation of B lymphocyte development and activation by the CD19/CD21/CD81/Leu 13 complex requires the cytoplasmic domain of CD19.

B lymphocyte development and function are regulated in part by the CD19 cell surface receptor complex, which is composed of at least four proteins; CD19, CD21 (CR2, complement receptor 2), CD81, and Leu 13. Because this complex has eight membrane-spanning domains and six cytoplasmic regions, determining the molecular basis for its function and signal transduction activities has not been straightforward. In this study, the contribution of the CD19 cytoplasmic domain to the in vivo function of the CD19/CD21/CD81/Leu 13 complex was assessed by generating CD19-deficient mice that expressed a transgene that encoded only the extracellular and transmembrane domains of CD19. Mice expressing this transgene were similar, if not identical, to CD19-deficient mice with abnormal B cell development, a lack of B-1 cells, increased surface IgM levels on B cells, modest mitogen responses, minimal serum Ig levels, and low humoral immune responses. The results of this study indicate that specific signals generated through the cytoplasmic domain of CD19 are essential for B lymphocyte development and function, and that CD19 is the dominant signaling component of the CD19 complex. Moreover, expression of the CD19 cytoplasmic domain is required for optimal signaling through the B cell Ag receptor complex.

Authors
Sato, S; Miller, AS; Howard, MC; Tedder, TF
MLA Citation
Sato, S, Miller, AS, Howard, MC, and Tedder, TF. "Regulation of B lymphocyte development and activation by the CD19/CD21/CD81/Leu 13 complex requires the cytoplasmic domain of CD19." J Immunol 159.7 (October 1, 1997): 3278-3287.
PMID
9317126
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
159
Issue
7
Publish Date
1997
Start Page
3278
End Page
3287

P- and L-selectin mediate distinct but overlapping functions in endotoxin-induced leukocyte-endothelial interactions in the rat mesenteric microcirculation.

Endotoxin is a potent stimulus of leukocyte infiltration, but the adhesion-related mechanisms responsible for LPS-induced cell recruitment events in vivo remain poorly characterized. Utilizing intravital microscopy, we examined the role of P- and L-selectin in LPS-induced inflammation. We demonstrated that superfusion of rat mesentery with LPS resulted in significant increases in both leukocyte rolling and adherence, which were maintained for at least 2 h. Pretreatment with a P-selectin neutralizing mAb only partially inhibited LPS-induced leukocyte rolling, but completely inhibited LPS-induced leukocyte adherence throughout the 2-h observation period. Pretreatment with an L-selectin neutralizing mAb dramatically inhibited LPS-induced increases in leukocyte rolling, but unlike the P-selectin mAb did not inhibit leukocyte adhesion. Fucoidin, which blocks both P- and L-selectin function, completely inhibited LPS-induced leukocyte rolling and adhesion. Consistent with previous studies, leukocyte rolling velocities on P-selectin were observed to be far less than velocities observed for leukocytes rolling on L-selectin in vivo. These data suggest that P-selectin plays a role in LPS-induced rolling and is essential for LPS-induced leukocyte adherence, while L-selectin functions in LPS-induced rolling, but not in adhesion.

Authors
Davenpeck, KL; Steeber, DA; Tedder, TF; Bochner, BS
MLA Citation
Davenpeck, KL, Steeber, DA, Tedder, TF, and Bochner, BS. "P- and L-selectin mediate distinct but overlapping functions in endotoxin-induced leukocyte-endothelial interactions in the rat mesenteric microcirculation." J Immunol 159.4 (August 15, 1997): 1977-1986.
PMID
9257864
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
159
Issue
4
Publish Date
1997
Start Page
1977
End Page
1986

Ligation of L-selectin through conserved regions within the lectin domain activates signal transduction pathways and integrin function in human, mouse, and rat leukocytes.

L-selectin is a cell surface adhesion receptor that mediates leukocyte rolling along vascular endothelium at sites of inflammation and lymphocyte attachment to endothelial cells within peripheral lymphoid tissues. Since ligation of L-selectin through its ligand recognition region may mimic physiologic ligand binding, a new panel of mAbs that engaged a conserved ligand-binding region within the lectin domains of human, mouse, and rat L-selectin were generated using L-selectin-deficient mice. Indeed, appropriate ligation of L-selectin generated transmembrane signals that resulted in immediate intercellular adhesion following cell-cell contact of lymphocytes, neutrophils, and L-selectin cDNA-transfected cells. Ab binding to only some epitopes within the lectin domain of L-selectin induced adhesion, while mAb binding to numerous other epitopes or other domains of L-selectin had no effect. PPME (yeast polyphosphomonoester core polysaccharide), a complex carbohydrate that mimics the natural L-selectin ligand, also induced potent intercellular adhesion. The induction of intercellular adhesion required cellular energy, an intact cytoskeleton, and cytoplasmic kinase activity as well as the membrane proximal and cytoplasmic domains of L-selectin. Therefore, ligation of L-selectin through specific ligand-binding epitopes identified by the mAbs generated in this study can generate transmembrane signals. Signaling through L-selectin may enhance leukocyte-endothelial cell interactions by serving as an activation/priming step during rolling, thereby promoting subsequent firm cell-cell adhesion in the presence of inflammatory mediators.

Authors
Steeber, DA; Engel, P; Miller, AS; Sheetz, MP; Tedder, TF
MLA Citation
Steeber, DA, Engel, P, Miller, AS, Sheetz, MP, and Tedder, TF. "Ligation of L-selectin through conserved regions within the lectin domain activates signal transduction pathways and integrin function in human, mouse, and rat leukocytes." J Immunol 159.2 (July 15, 1997): 952-963.
PMID
9218616
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
159
Issue
2
Publish Date
1997
Start Page
952
End Page
963

Generation of dendritic cells in vitro from peripheral blood mononuclear cells with granulocyte-macrophage-colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha for use in cancer immunotherapy.

OBJECTIVE: The purpose of the study was to characterize the requirements in terms of precursors, developmental pathways, and media for the generation of large numbers of mature dendritic cells (DC) under conditions acceptable for use in adjuvant, active immunotherapy strategies for surgically treated malignancies. SUMMARY BACKGROUND DATA: Although limited previously by the small numbers accessible, DC-based immunotherapies for malignancy have become more realistic with the development of methods for efficiently generating larger numbers of DC from peripheral blood mononuclear cells (PBMC) in vitro, but these methods rely on clinically unacceptable culture conditions (such as inclusion of fetal bovine serum), necessitating the development of methods for generating functionally equivalent DC in serum-free conditions. METHODS: Plastic-adherent PBMC (from healthy donors and patients with cancer) were incubated for 7 days with granulocyte-macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) with and without tumor necrosis factor-alpha (TNF-alpha) in fetal bovine serum-containing and serum-free media and were analyzed by Wright's stain for morphology, flow cytometry for phenotype, and mixed lymphocyte reaction for allostimulatory function. RESULTS: Growth in either serum-containing or serum-free media supplemented with GM-CSF and IL-4 yielded a similarly heterogeneous population of cells, 6% to 10% of which had the morphology (large cells with thin projections), immunophenotype (including CD83+), and function of mature DC. Tumor necrosis factor-alpha significantly augmented the number of these mature DC, whereas preculture depletion of CD14+ PBMC virtually eliminated them. CONCLUSIONS: Generation of mature DC in the authors' serum-free clinically applicable conditions is similar to serum-containing conditions and requires CD14+ precursors, differentiation through a CD14-CD83- immature stage under the influence of GM-CSF and IL-4, and maturation into a CD83+ DC under the influence of TNF-alpha.

Authors
Morse, MA; Zhou, LJ; Tedder, TF; Lyerly, HK; Smith, C
MLA Citation
Morse, MA, Zhou, LJ, Tedder, TF, Lyerly, HK, and Smith, C. "Generation of dendritic cells in vitro from peripheral blood mononuclear cells with granulocyte-macrophage-colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha for use in cancer immunotherapy." Ann Surg 226.1 (July 1997): 6-16.
PMID
9242332
Source
pubmed
Published In
Annals of Surgery
Volume
226
Issue
1
Publish Date
1997
Start Page
6
End Page
16

L-selectin is involved in lymphocyte migration to sites of inflammation in the skin: delayed rejection of allografts in L-selectin-deficient mice.

Adhesion of leukocytes to vascular endothelium is crucial for leukocyte migration into tissues. The contributions of L-selectin, P-selectin, and ICAM-1 to interactions between lymphocytes and endothelium was examined using allogeneic skin graft rejection as a model of cutaneous inflammation. L-selectin-deficient (L-selectin(-/-)) mice rejected both primary and secondary allogeneic (BALB/c) skin grafts significantly more slowly than L-selectin(+/+) littermates. Furthermore, skin graft rejection remained significantly delayed in L-selectin(-/-) mice, despite placement of grafts 7 days after i.p. immunization with allogeneic cells, when CTL responses in L-selectin(-/-) mice and L-selectin(+/+) littermates were confirmed to be equivalent. Indeed, specific CTL responses to BALB/c splenocytes were normal or elevated in L-selectin(-/-) mice following either skin grafts or immunization. However, the number of T lymphocytes within allogeneic grafts was lower in L-selectin(-/-) mice as compared with L-selectin(+/+) littermates. Therefore, delayed rejection of skin grafts by L-selectin(-/-) mice reflects impaired migration of effector cells into the graft rather than delayed or impaired generation of a CTL response. In contrast to L-selectin(-/-) mice, P-selectin-deficient and ICAM-1-deficient mice rejected allogeneic skin grafts normally. These findings delineate an important role for L-selectin in lymphocyte recruitment to cutaneous sites of inflammation.

Authors
Tang, ML; Hale, LP; Steeber, DA; Tedder, TF
MLA Citation
Tang, ML, Hale, LP, Steeber, DA, and Tedder, TF. "L-selectin is involved in lymphocyte migration to sites of inflammation in the skin: delayed rejection of allografts in L-selectin-deficient mice." J Immunol 158.11 (June 1, 1997): 5191-5199.
PMID
9164936
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
158
Issue
11
Publish Date
1997
Start Page
5191
End Page
5199

Chemoattractant receptor-induced phosphorylation of L-selectin.

The selectin adhesion molecules and chemoattractant receptors synergistically regulate leukocyte migration into lymphoid tissues and sites of inflammation, but little is known about how these families of receptors modulate each other's function. In this study, L-selectin was found to be phosphorylated in lymphoblastoid cell lines, and phosphorylation was enhanced by phorbol ester (phorbol 12-myristate 13-acetate (PMA)) treatment. Interactions between L-selectin and chemoattractant receptors were therefore examined using transfected rat basophilic leukemia cell lines (RBL-2H3) that expressed human L-selectin along with human leukocyte chemoattractant receptors. L-selectin was rapidly phosphorylated in cells treated with chemoattractants, thrombin, IgE receptor agonists, or PMA. Pertussis toxin or the protein kinase C inhibitor, staurosporine, completely blocked chemoattractant receptor-induced phosphorylation of L-selectin. PMA-induced phosphorylation was on serine residues within the cytoplasmic tail of L-selectin that have been well conserved during recent evolution. Although L-selectin phosphorylation was not essential for basal levels of adhesion through L-selectin in transformed cell lines, the rapid increase in ligand binding activity of L-selectin that occurs following leukocyte activation was blocked by staurosporine. These results demonstrate that L-selectin can be phosphorylated following engagement of chemoattractant receptors and suggest that this may be a physiologically relevant mechanism for the synergistic regulation of these receptors during leukocyte migration.

Authors
Haribabu, B; Steeber, DA; Ali, H; Richardson, RM; Snyderman, R; Tedder, TF
MLA Citation
Haribabu, B, Steeber, DA, Ali, H, Richardson, RM, Snyderman, R, and Tedder, TF. "Chemoattractant receptor-induced phosphorylation of L-selectin." J Biol Chem 272.21 (May 23, 1997): 13961-13965.
PMID
9153259
Source
pubmed
Published In
The Journal of biological chemistry
Volume
272
Issue
21
Publish Date
1997
Start Page
13961
End Page
13965

CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19.

Establishing signal transduction thresholds that regulate B lymphocyte responses to foreign Ags and tolerance to self Ags is critical for humoral immune responses. The effects of altered signaling thresholds in B lymphocytes were examined in CD19-deficient mice and transgenic mice that expressed human CD19 at varying densities. Human CD19 restored normal B cell function and development to CD19-deficient mice when expressed at levels comparable to those of circulating human B cells. While CD19 expression levels were found to be developmentally regulated and tightly controlled in normal mice, two- or threefold changes in cell surface CD19 expression in transgenic mice dramatically affected B cell development, mitogen responses, serum Ig levels, humoral immune responses, and germinal center formation. B cells from mice that overexpressed CD19 also had decreased levels of surface IgM and a cell surface phenotype consistent with increased signaling in these cells. These results suggest that CD19 may serve similar functions in humans and mice and that CD19 defines signaling thresholds in vivo for the Ag receptor as well as other cell surface receptors that regulate B lymphocyte selection, activation, and differentiation.

Authors
Sato, S; Steeber, DA; Jansen, PJ; Tedder, TF
MLA Citation
Sato, S, Steeber, DA, Jansen, PJ, and Tedder, TF. "CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19." J Immunol 158.10 (May 15, 1997): 4662-4669.
PMID
9144478
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
158
Issue
10
Publish Date
1997
Start Page
4662
End Page
4669

L-selectin shedding does not regulate human neutrophil attachment, rolling, or transmigration across human vascular endothelium in vitro.

Current models of the multistep adhesion cascade for leukocyte-endothelial interactions predict loss of L-selectin from the leukocyte surface before transendothelial migration. We have tested this hypothesis using in vitro adhesion and transendothelial migration assays and a zinc-dependent metalloproteinase inhibitor, Ro 31-9790 (N-2-((2s)-[(hydroxycarbamoyl)methyl)-4-methylvaleryl]-N-1,3 -dimethyl-L-valinamide), which prevents chemoattractant-induced (e.g., IL-8, FMLP, C5a, platelet-activating factor) L-selectin endoproteolytic cleavage from isolated human neutrophils. Inhibitor and vehicle-treated neutrophils exhibited identical behavior during both adhesive interactions with 4- and 24-h TNF-alpha-activated HUVEC monolayers under flow, (including rate of initial attachment, rolling velocities, stable adhesion, and transmigration) and in static adhesion assays. Flow cytometric analysis of transmigrated neutrophils with mAb to L-selectin revealed that vehicle treated neutrophils had minimal detectable surface L-selectin, whereas inhibitor-treated neutrophils retained comparable levels of L-selectin on their surface as neutrophils maintained at 37 degrees C. In addition, mAb to L-selectin that induce rapid shape change and homotypic adhesion (LAM1-116) did not enhance the rate or extent of neutrophil transmigration under flow or static conditions. Neutrophils preincubated with LAM 1-116 displayed similar behavior to neutrophils preincubated with the control anti-L-selectin mAb, LAM1-101. In summary, these results demonstrate that there is no requirement for L-selectin to be shed from the surface of neutrophils before, or during, their migration across endothelial monolayers, and that prevention of surface L-selectin proteolytic cleavage does not enhance or inhibit neutrophil-endothelial cell adhesive interactions.

Authors
Allport, JR; Ding, HT; Ager, A; Steeber, DA; Tedder, TF; Luscinskas, FW
MLA Citation
Allport, JR, Ding, HT, Ager, A, Steeber, DA, Tedder, TF, and Luscinskas, FW. "L-selectin shedding does not regulate human neutrophil attachment, rolling, or transmigration across human vascular endothelium in vitro." J Immunol 158.9 (May 1, 1997): 4365-4372.
PMID
9127000
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
158
Issue
9
Publish Date
1997
Start Page
4365
End Page
4372

Antibody to VLA-4, but not to L-selectin, protects neuronal M2 muscarinic receptors in antigen-challenged guinea pig airways.

Antigen challenge of sensitized guinea pigs decreases the function of inhibitory M2 muscarinic autoreceptors on parasympathetic nerves in the lung, potentiating vagally induced bronchoconstriction. Loss of M2 receptor function is associated with the accumulation of eosinophils around airway nerves. To determine whether recruitment of eosinophils via expression of VLA-4 and L-selectin is critical for loss of M2 receptor function, guinea pigs were pretreated with monoclonal antibodies to VLA-4 (HP1/2) or L-selectin (LAM1-116). Guinea pigs were sensitized and challenged with ovalbumin, and M2 receptor function was tested. In controls, blockade of neuronal M2 muscarinic receptors by gallamine potentiated vagally induced bronchoconstriction, while in challenged animals this effect was markedly reduced, confirming M2 receptor dysfunction. Pretreatment with HP1/2, but not with LAM1-116, protected M2 receptor function in the antigen-challenged animals. HP1/2 also inhibited the development of hyperresponsiveness, and selectively inhibited accumulation of eosinophils in the lungs as measured by lavage and histology. Thus, inhibition of eosinophil influx into the lungs protects the function of M2 muscarinic receptors, and in so doing, prevents hyperresponsiveness in antigen-challenged guinea pigs.

Authors
Fryer, AD; Costello, RW; Yost, BL; Lobb, RR; Tedder, TF; Steeber, DA; Bochner, BS
MLA Citation
Fryer, AD, Costello, RW, Yost, BL, Lobb, RR, Tedder, TF, Steeber, DA, and Bochner, BS. "Antibody to VLA-4, but not to L-selectin, protects neuronal M2 muscarinic receptors in antigen-challenged guinea pig airways." J Clin Invest 99.8 (April 15, 1997): 2036-2044.
PMID
9109449
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
99
Issue
8
Publish Date
1997
Start Page
2036
End Page
2044
DOI
10.1172/JCI119372

Leukocyte rolling in Peyer's Patch (PP) high endothelial venules (HEV) occurs at different characteristic velocities in L-selectin- and beta(7) integrin-deficient mice

Authors
Kunkel, EJ; Wagner, N; Tedder, TF; Ley, K
MLA Citation
Kunkel, EJ, Wagner, N, Tedder, TF, and Ley, K. "Leukocyte rolling in Peyer's Patch (PP) high endothelial venules (HEV) occurs at different characteristic velocities in L-selectin- and beta(7) integrin-deficient mice." FASEB JOURNAL 11.3 (February 28, 1997): 1968-1968.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
11
Issue
3
Publish Date
1997
Start Page
1968
End Page
1968

Neutrophil margination, sequestration, and emigration in the lungs of L-selectin-deficient mice.

These studies tested the hypothesis that L-selectin plays a role in neutrophil traffic in the lungs, particularly in neutrophil margination, sequestration, and emigration, using L-selectin-deficient mice. No defect in neutrophil margination within either capillaries or arterioles and venules was observed in uninflamed lungs of L-selectin-deficient mice. The initial rapid sequestration of neutrophils within the pulmonary capillaries 1 min after intravascular injection of complement fragments was not prevented. In contrast, L-selectin did contribute to the prolonged neutrophil sequestration (> or = 5 min). Interestingly, neutrophil accumulation within noncapillary microvessels required L-selectin at both 1 and 5 min after complement injection. During bacterial pneumonias, L-selectin played a role in neutrophil accumulation within noncapillary microvessels in response to either Escherichia coli or Streptococcus pneumoniae and within capillaries in response to E. coli but not S. pneumoniae. However, L-selectin was not required for emigration of neutrophils or edema in response to either organism. These studies demonstrate a role for L-selectin in the prolonged sequestration of neutrophils in response to intravascular complement fragments, in the intracapillary accumulation of neutrophils during E. coli-induced pneumonia, and in the accumulation of neutrophils within noncapillary microvessels when induced by either intravascular complement fragments or

Authors
Doyle, NA; Bhagwan, SD; Meek, BB; Kutkoski, GJ; Steeber, DA; Tedder, TF; Doerschuk, CM
MLA Citation
Doyle, NA, Bhagwan, SD, Meek, BB, Kutkoski, GJ, Steeber, DA, Tedder, TF, and Doerschuk, CM. "Neutrophil margination, sequestration, and emigration in the lungs of L-selectin-deficient mice." J Clin Invest 99.3 (February 1, 1997): 526-533.
PMID
9022088
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
99
Issue
3
Publish Date
1997
Start Page
526
End Page
533
DOI
10.1172/JCI119189

The CD19-CD21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity.

Authors
Tedder, TF; Inaoki, M; Sato, S
MLA Citation
Tedder, TF, Inaoki, M, and Sato, S. "The CD19-CD21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity." Immunity 6.2 (February 1997): 107-118. (Review)
PMID
9047233
Source
pubmed
Published In
Immunity
Volume
6
Issue
2
Publish Date
1997
Start Page
107
End Page
118

Role of L-selectin in lymphocyte migration to cutaneous sites of inflammation.

Authors
Tang, MLK; Hale, LP; Steeber, DA; Tedder, TF
MLA Citation
Tang, MLK, Hale, LP, Steeber, DA, and Tedder, TF. "Role of L-selectin in lymphocyte migration to cutaneous sites of inflammation." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 99.1 (January 1997): 1729-1729.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
99
Issue
1
Publish Date
1997
Start Page
1729
End Page
1729

Impaired inflammatory responses in mice deficient in both L-selectin and intercellular adhesion molecule-1.

Authors
Steeber, DA; Green, NE; Palmer, SM; Tang, MLK; Tedder, TF
MLA Citation
Steeber, DA, Green, NE, Palmer, SM, Tang, MLK, and Tedder, TF. "Impaired inflammatory responses in mice deficient in both L-selectin and intercellular adhesion molecule-1." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 99.1 (January 1997): 479-479.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
99
Issue
1
Publish Date
1997
Start Page
479
End Page
479

Chemoattractant receptor-induced phosphorylation of L-selectin.

Authors
Haribabu, B; Steeber, DA; Ali, H; Richardson, RM; Tedder, TF; Snyderman, R
MLA Citation
Haribabu, B, Steeber, DA, Ali, H, Richardson, RM, Tedder, TF, and Snyderman, R. "Chemoattractant receptor-induced phosphorylation of L-selectin." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 99.1 (January 1997): 1005-1005.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
99
Issue
1
Publish Date
1997
Start Page
1005
End Page
1005

CD22 is both a negative and positive regulator of B lymphocyte antigen receptor signaling.

Authors
Sato, S; Miller, AS; Bock, CB; Inaoki, M; Jansen, PJ; Tang, MLK; Tedder, TF
MLA Citation
Sato, S, Miller, AS, Bock, CB, Inaoki, M, Jansen, PJ, Tang, MLK, and Tedder, TF. "CD22 is both a negative and positive regulator of B lymphocyte antigen receptor signaling." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 99.1 (January 1997): 881-881.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
99
Issue
1
Publish Date
1997
Start Page
881
End Page
881

L-selectin binds to P-selectin glycoprotein ligand-1 on leukocyte.

Authors
Tu, L; Chen, A; Delahunty, M; Moore, K; Watson, SR; McEver, RP; Tedder, TF
MLA Citation
Tu, L, Chen, A, Delahunty, M, Moore, K, Watson, SR, McEver, RP, and Tedder, TF. "L-selectin binds to P-selectin glycoprotein ligand-1 on leukocyte." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 99.1 (January 1997): 1917-1917.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
99
Issue
1
Publish Date
1997
Start Page
1917
End Page
1917

CD19 regulates peripheral tolerance in B lymphocytes.

Authors
Inaoki, M; Sato, S; Goodnow, CC; Tedder, TF
MLA Citation
Inaoki, M, Sato, S, Goodnow, CC, and Tedder, TF. "CD19 regulates peripheral tolerance in B lymphocytes." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 99.1 (January 1997): 1521-1521.
Source
wos-lite
Published In
Journal of Allergy and Clinical Immunology
Volume
99
Issue
1
Publish Date
1997
Start Page
1521
End Page
1521

CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling.

The development of B lymphocytes is a highly regulated process that depends in part on lineage-specific cell surface molecules. In addition, transmembrane signals generated through the B cell antigen receptor and other surface molecules regulate B cell responses to foreign antigens. Recent studies reveal CD22 to be a functionally significant receptor during these processes. CD22 is first expressed in the cytoplasm of pro-B and pre-B cells, and on the surface as B cells mature to become IgD+. CD22 is a member of the Ig superfamily that serves as an adhesion receptor for sialic acid-bearing ligands expressed on erythrocytes and all leukocyte classes. In addition to its potential role as a mediator of intercellular interactions, signal transduction through CD22 can activate B cells and modulate antigen receptor signaling in vitro. CD22 signaling is mediated via interactions with a number of kinases and phosphatases that bind the cytoplasmic domain through phosphorylated tyrosine residues located within consensus TAM and TIM motifs. The phenotype of CD22-deficient mice suggests that CD22 is primarily involved in the generation of mature B cells within the bone marrow, blood, and marginal zones of lymphoid tissues. Most notable in CD22-deficient mice is a significant diminution of surface Ig levels in these B cell subpopulations, which suggests that CD22 functions in vivo to adjust the signaling threshold of cell surface antigen receptors. A further understanding of CD22 function is required and may reveal roles for CD22 in disease susceptibility or the development of autoimmunity.

Authors
Tedder, TF; Tuscano, J; Sato, S; Kehrl, JH
MLA Citation
Tedder, TF, Tuscano, J, Sato, S, and Kehrl, JH. "CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling." Annu Rev Immunol 15 (1997): 481-504. (Review)
PMID
9143697
Source
pubmed
Published In
Annual Review of Immunology
Volume
15
Publish Date
1997
Start Page
481
End Page
504
DOI
10.1146/annurev.immunol.15.1.481

Leukocyte rolling in Peyer's Patch (PP) high endothelial venules (HEV) occurs at different characteristic velocites in L-selectin- and β7 integrin-deficient mice

Both L-selectin and β7 integrins have been implicated in lymphocyte homing to Peyer's Patches in vivo. In order to understand the contributions of both L-selectin and β7 integrins to leukocyte rolling in PP, we have measured the leukocyte rolling flux fraction and rolling velocity in hemodynamically similar PP HEV using in vivo epiluminescence intravital microscopy in wild-type, L-selectin-deficient (L -/-), and β7 integrin-deficient (β7 -/-) mice. Intravascular leukocytes were stained using acridine red and average blood flow velocities in PP HEV were measured using fluorescent beads. The rolling flux fractions in wild-type (98±15%) and β7 -/- (85±10%) mice were not statistically different. In both wild-type and β7 -/- mice, the rolling flux fraction was reduced by 80-90% with the blocking L-selectin mAb MEL-14 (p<0.01). Conversely, in L -/- mice, the rolling flux fraction was only 19±6% (p<0.01 vs. wild-type and β7 -/- mice). The rolling velocity distribution in wild-type mice was bimodal, with peaks around 30 and 95 μm/s. β7 -/- mice had a velocity distribution with one peak at ∼85 μm/s. Conversely, L -/- mice had a unimodal velocity distribution with the peak at ∼25 μm/s. Together, these data highlight a role for β7 integrins in mediating leukocyte rolling in PP HEV in vivo.

Authors
Kunkel, EJ; Wagner, N; Tedder, TF; Ley, K
MLA Citation
Kunkel, EJ, Wagner, N, Tedder, TF, and Ley, K. "Leukocyte rolling in Peyer's Patch (PP) high endothelial venules (HEV) occurs at different characteristic velocites in L-selectin- and β7 integrin-deficient mice." FASEB Journal 11.3 (1997): A339-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
11
Issue
3
Publish Date
1997
Start Page
A339

Humoral immune responses in L-selectin-deficient mice.

L-selectin regulates lymphocyte migration by mediating lymphocyte attachment to high endothelial venules of peripheral lymph nodes (PLN). L-selectin-deficient mice display a 70 to 90% reduction in the number of lymphocytes within PLNs and a 30 to 55% increase in spleen cellularity. The altered distribution of lymphocyte subpopulations in L-selectin-deficient mice resulted in significantly elevated serum IgM and IgG1 levels and augmented humoral immune responses to T cell-independent and T cell-dependent Ags following i.p. immunization. By contrast, s.c. immunization of L-selectin-deficient mice with a T cell-dependent Ag resulted in serum IgM responses that were 40% lower when compared with wild-type littermates on day 7, while primary IgG responses were essentially absent. Most serum Ig responses were normal by day 14 and secondary responses were higher in L-selectin-deficient mice. Although lymphocytes from L-selectin-deficient mice were unable to enter Ag-stimulated lymph nodes through high endothelial venules, the cellularity of draining lymph nodes increased significantly following immunization. Germinal centers developed rapidly following immunization, although PLNs of L-selectin-deficient mice contained few follicles. Germinal centers within PLNs and the spleen were also consistently much larger and more well defined in L-selectin-deficient mice when compared with wild-type littermates. These results confirm that lymphocyte migration plays an important role in the initiation of humoral responses and demonstrate complementary and overlapping roles for the spleen and other peripheral lymphoid tissues in the generation of immune responses.

Authors
Steeber, DA; Green, NE; Sato, S; Tedder, TF
MLA Citation
Steeber, DA, Green, NE, Sato, S, and Tedder, TF. "Humoral immune responses in L-selectin-deficient mice." J Immunol 157.11 (December 1, 1996): 4899-4907.
PMID
8943394
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
157
Issue
11
Publish Date
1996
Start Page
4899
End Page
4907

Velocity differences between L- and P-selectin-dependent neutrophil rolling in venules of mouse cremaster muscle in vivo.

After surgical trauma, leukocyte rolling is initially normal in L-selectin-deficient mice and reduced at later times, whereas leukocyte rolling is initially absent in P-selectin-deficient mice but induced later. Here, we examined the possibility that P- and L-selectin support rolling at different characteristic velocities using intravital microscopy of venules of the exteriorized cremaster muscle venules of wild type (WT) and P- and L-selectin-deficient mice. At > 50 min after exteriorization, rolling in P-selectin-deficient mice occurred at significantly higher velocities (129 +/- 89 microns/s) than in WT mice (49 +/- 23 microns/s). Rolling velocity distribution in L-selectin-deficient mice was similar to WT mice immediately after exteriorization. Histological examination of Giemsa-stained whole-mount preparations in cremaster muscle venules revealed that the majority of rolling cells (approximately 90% in all genotypes) were granulocytes. We conclude that P-selectin mediates leukocyte rolling at velocities < 50 microns/s, whereas L-selectin sustains more rapid rolling. Under physiological conditions, P- and L-selectin synergize to support rolling at velocities between 20 and 70 microns/s as seen in WT mice.

Authors
Jung, U; Bullard, DC; Tedder, TF; Ley, K
MLA Citation
Jung, U, Bullard, DC, Tedder, TF, and Ley, K. "Velocity differences between L- and P-selectin-dependent neutrophil rolling in venules of mouse cremaster muscle in vivo." Am J Physiol 271.6 Pt 2 (December 1996): H2740-H2747.
PMID
8997339
Source
pubmed
Published In
The American journal of physiology
Volume
271
Issue
6 Pt 2
Publish Date
1996
Start Page
H2740
End Page
H2747

CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: altered signaling in CD22-deficient mice.

B cell activation following antigen receptor cross-linking can be augmented in vitro by ligation of cell surface CD22, which associates with the SHP1 protein tyrosine phosphatase. The targeted deletion of CD22 in mice demonstrated that CD22 differentially regulates antigen receptor signaling in resting and antigen-stimulated B lymphocytes. B cells from CD22-deficient mice exhibited the cell surface phenotype and augmented intracellular calcium responses characteristic of chronically stimulated B cells, as occurs in SHP1-defective mice. Thus, CD22 negatively regulates antigen receptor signaling in the absence of antigen. However, activation of CD22-deficient B lymphocytes by prolonged IgM cross-linking resulted in modest B cell proliferation, demonstrating that CD22 positively regulates antigen receptor signaling in the presence of antigen.

Authors
Sato, S; Miller, AS; Inaoki, M; Bock, CB; Jansen, PJ; Tang, ML; Tedder, TF
MLA Citation
Sato, S, Miller, AS, Inaoki, M, Bock, CB, Jansen, PJ, Tang, ML, and Tedder, TF. "CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: altered signaling in CD22-deficient mice." Immunity 5.6 (December 1996): 551-562.
PMID
8986715
Source
pubmed
Published In
Immunity
Volume
5
Issue
6
Publish Date
1996
Start Page
551
End Page
562

Velocity differences between L- and P-selectin-dependent neutrophil rolling in venules of mouse cremaster muscle in vivo

Authors
Jung, U; Bullard, DC; Tedder, TF; Ley, K
MLA Citation
Jung, U, Bullard, DC, Tedder, TF, and Ley, K. "Velocity differences between L- and P-selectin-dependent neutrophil rolling in venules of mouse cremaster muscle in vivo." AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 271.6 (December 1996): H2740-H2747.
Source
wos-lite
Published In
American journal of physiology. Heart and circulatory physiology
Volume
271
Issue
6
Publish Date
1996
Start Page
H2740
End Page
H2747

CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity.

CD19 serves as a cell surface response regulator that establishes signaling thresholds critical for B lymphocyte development and activation. B lymphocytes from CD19-deficient mice are hyporesponsive to transmembrane signals, while B lymphocytes from mice that overexpress CD19 to even a small extent (25% increase) become hyperresponsive. The B-1 subpopulation of B lymphocytes is particularly sensitive to CD19 regulation, since their development is severely decreased in CD19-deficient mice. The effect of altered CD19 expression levels on the development of B cells was therefore examined using transgenic mice that express varying levels of cell surface CD19. In this study, immature B cells within the bone marrow of wild-type mice were found to specifically up-regulate CD19 expression levels by twofold as they mature, while CD5+ B cells within the spleen and peritoneum expressed even higher levels of CD19. The development of CD5+ B cells was severely decreased in CD19-deficient mice, while there was a linear correlation between increased CD19 expression levels and the increased frequency of CD5+ B cells within the peritoneum and spleen. In fact, CD5+ B cells became a major B lymphocyte population in mice that overexpressed CD19. Increased expression of CD19 also correlated with increased levels of endogenous anti-DNA Abs and rheumatoid factor. These results indicate that up-regulated expression of CD19 is functionally important for B cell development and that CD19 establishes signaling thresholds that regulate the generation of B-1 lymphocytes as well as the development of autoantibodies.

Authors
Sato, S; Ono, N; Steeber, DA; Pisetsky, DS; Tedder, TF
MLA Citation
Sato, S, Ono, N, Steeber, DA, Pisetsky, DS, and Tedder, TF. "CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity." J Immunol 157.10 (November 15, 1996): 4371-4378.
PMID
8906812
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
157
Issue
10
Publish Date
1996
Start Page
4371
End Page
4378

L-selectin binds to P-selectin glycoprotein ligand-1 on leukocytes: interactions between the lectin, epidermal growth factor, and consensus repeat domains of the selectins determine ligand binding specificity.

The selectins mediate cellular interactions by binding carbohydrate determinants present on a limited number of glycoprotein ligands. L-selectin binds multiple ligands expressed on endothelial cells, while P-selectin interacts exclusively with P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes. In this study, L-selectin was shown to bind leukocytes through the P-selectin ligand, PSGL-1, although at lower levels than P-selectin. L-selectin binding to PSGL-1 is specific since it was blocked by Abs to L-selectin or PSGL-1, required appropriate glycosylation of PSGL-1, and was Ca2+ dependent. The contributions of the extracellular domains of the selectins to ligand binding was assessed using a panel of chimeric selectins created by exchange of domains between L-selectin and P- or E-selectin. The lectin and epidermal growth factor domains of L- and P-selectin contributed significantly to binding through similar, if not identical, regions of PSGL-1. The different chimeric selectins revealed that the lectin domain was the dominant determinant for ligand binding, while cooperative interactions between the lectin, epidermal growth factor, and short consensus repeat domains of the selectins also modified ligand binding specificity. L-selectin binding to PSGL-1 expressed by leukocytes may mediate neutrophil rolling on stationary leukocytes bound to cytokine-induced endothelial cells, which was previously reported to be a L-selectin-dependent process.

Authors
Tu, L; Chen, A; Delahunty, MD; Moore, KL; Watson, SR; McEver, RP; Tedder, TF
MLA Citation
Tu, L, Chen, A, Delahunty, MD, Moore, KL, Watson, SR, McEver, RP, and Tedder, TF. "L-selectin binds to P-selectin glycoprotein ligand-1 on leukocytes: interactions between the lectin, epidermal growth factor, and consensus repeat domains of the selectins determine ligand binding specificity." J Immunol 157.9 (November 1, 1996): 3995-4004.
PMID
8892633
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
157
Issue
9
Publish Date
1996
Start Page
3995
End Page
4004

Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits.

Leukocyte adhesion molecule (LAM) blockade reduces ischemia-reperfusion injury. We tested the hypothesis that a monoclonal antibody (MAb) that recognizes a functional epitope of L-selectin would decrease hemorrhagic shock-induced reperfusion injury. Anesthetized rabbits were subjected to 2 h of hemorrhagic shock (cardiac output reduced to 30% of baseline), then given one of the following treatments: MAbs that recognize functional domains of L-selectin (LAM1-3), CD18 (60.3), MAbs that recognize a nonfunctional domain on L-selectin (LAM1-14), or saline, immediately before resuscitation with shed blood. Additional fluids were administered as needed to maintain cardiac output at baseline levels for 6 h. The cumulative fluid resuscitation after MAb LAM1-3 (58 +/- 34 ml/kg) was not significantly different from after MAb 60.3 (21 +/- 24 ml/kg) or MAb LAM1-14 (66 +/- 51 ml/kg), but it was significantly less than saline-treated controls (142 +/- 142 ml/kg). However, two animals treated with MAb LAM1-14 died before 6 h. If their resuscitation volumes are projected to 6 h by linear regression, then the LAM1-14-treated group required significantly greater volume (101 +/- 99 ml/kg) than the MAb LAM1-3-treated group. We conclude that MAbs to a functional domain on L-selectin are protective against reperfusion-injury following hemorrhagic shock.

Authors
Ramamoorthy, C; Sharar, SR; Harlan, JM; Tedder, TF; Winn, RK
MLA Citation
Ramamoorthy, C, Sharar, SR, Harlan, JM, Tedder, TF, and Winn, RK. "Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits." Am J Physiol 271.5 Pt 2 (November 1996): H1871-H1877.
PMID
8945903
Source
pubmed
Published In
The American journal of physiology
Volume
271
Issue
5 Pt 2
Publish Date
1996
Start Page
H1871
End Page
H1877

Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits

Authors
Ramamoorthy, C; Sharar, SR; Harlan, JM; Tedder, TF; Winn, RK
MLA Citation
Ramamoorthy, C, Sharar, SR, Harlan, JM, Tedder, TF, and Winn, RK. "Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits." AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 271.5 (November 1996): H1871-H1877.
Source
wos-lite
Published In
American journal of physiology. Heart and circulatory physiology
Volume
271
Issue
5
Publish Date
1996
Start Page
H1871
End Page
H1877

P-selectin glycoprotein ligand-1 is broadly expressed in cells of myeloid, lymphoid, and dendritic lineage and in some nonhematopoietic cells.

P-selectin glycoprotein ligand-1 (PSGL-1) is a muclin-like glycoportein ligand for P- and E-selectin on myeloid cells and a subset of lymphocytes. We used flow cytometry and immunohistochemistry to examine expression of PSGL-1 on minor leukocyte populations, differentiating hematopoletic cells, and nonhematopoietic tissues using two monoclonal antibodies to distinct protein epitopes on PSGL-1. In the bone marrow, PSGL-1 was expressed on myeloid cells from the myeloblast stage to the segmented neutrophil, but was not detected on erythroblasts or megakaryocytes. All types of circulating myeloid cells expressed PSGL-1, and PSGL-1 was retained after extravasation of myetoid cells into tissues. PSGL-1 was also expressed on circulating dendritic cells, monocyte-derived dendritic cells, dendritic cells in lymphoid tissues and epidermis, and follicular dendritic cells. All types of lymphoid cells examined expressed PSGK-1, including immature and mature thymocytes, naive and memory T cells, gamma/delta T cells, netural killer cells, B cells and CD34+ progenitor cells. However, PSGL-1 levels were substantially lower on tonsillar lymphocytes than on circulating lymphocytes, suggesting that PSGL-1 expression is down regulated during or after entry of lymphocytes into secondary lymphoid tissue. Although PSGL-1 antigen was detected primarily on hamatopoietic cells, it was also present on time epithelium of the fallopian tube. Furthermore, PSGL-1 antigen gen was detected sporadically on microvascular endothelium in some pathologic tissues. This suggests that PSGL-1 may have functions other than mediating leukocyte adhersion.

Authors
Laszik, Z; Jansen, PJ; Cummings, RD; Tedder, TF; McEver, RP; Moore, KL
MLA Citation
Laszik, Z, Jansen, PJ, Cummings, RD, Tedder, TF, McEver, RP, and Moore, KL. "P-selectin glycoprotein ligand-1 is broadly expressed in cells of myeloid, lymphoid, and dendritic lineage and in some nonhematopoietic cells." Blood 88.8 (October 15, 1996): 3010-3021.
PMID
8874199
Source
pubmed
Published In
Blood
Volume
88
Issue
8
Publish Date
1996
Start Page
3010
End Page
3021

Analysis of the CD19 and CD20 antibodies in the B cell section of the workshop.

Authors
Sato, S; Ono, N; Tedder, TF
MLA Citation
Sato, S, Ono, N, and Tedder, TF. "Analysis of the CD19 and CD20 antibodies in the B cell section of the workshop." TISSUE ANTIGENS 48.4-II (October 1996): BC301-BC301.
Source
wos-lite
Published In
Tissue Antigens
Volume
48
Issue
4-II
Publish Date
1996
Start Page
BC301
End Page
BC301

L-selectin (CD62L) blockade does not impair peritoneal neutrophil emigration or subcutaneous host defense to bacteria in rabbits.

Neutrophil (PMN) recruitment into systemic inflammatory sites in vivo is thought to be initiated by selectin-mediated endothelial adherence. We explored the role of L-selectin (CD62L) in leukocyte emigration following instillation of bacteria into the peritoneum or s.c. skin in rabbits. Pretreatment with blocking mAb against L-selectin (LAM1.3) reduced peritoneal PMN emigration 4 h after i.p. inoculation with 10(10) CFU of Escherichia coli by only 17% compared with animals receiving a nonblocking L-selectin mAb (LAM1.14). Peritoneal PMNs from saline-treated rabbits demonstrated a complete absence of L-selectin, whereas those from LAM1.3-treated animals retained 43% of their baseline L-selectin expression. This suggests that L-selectin shedding is not a requisite event for PMN emigration under these conditions. In rabbits given s.c. inoculations with either Staphylococcus aureus or E coli, pretreatment with mAb LAM1.3 did not significantly impair PMN emigration at 24 h, nor increase the incidence, size, or associated mortality of resulting abscesses at 7 days compared with animals receiving nonblocking mAb LAM1.14. We conclude that: 1) mAb blockade of L-selectin in vivo only modestly affects acute, E. coli-induced peritoneal PMN emigration; and 2) L-selectin blockade does not increase infectious sequelae associated with s.c. bacterial inoculation. These findings of only mildly reduced PMN emigration into the peritoneum and no alteration in s.c. host defense differ from those reported with L-selectin blockade under other, nonbacterial inflammatory conditions, and suggest that redundant selectin-mediated mechanisms (P- and E-selectin) are sufficient for normal PMN emigration in response to bacterial stimulation.

Authors
Sharar, SR; Chapman, NN; Flaherty, LC; Harlan, JM; Tedder, TF; Winn, RK
MLA Citation
Sharar, SR, Chapman, NN, Flaherty, LC, Harlan, JM, Tedder, TF, and Winn, RK. "L-selectin (CD62L) blockade does not impair peritoneal neutrophil emigration or subcutaneous host defense to bacteria in rabbits." J Immunol 157.6 (September 15, 1996): 2555-2563.
PMID
8805657
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
157
Issue
6
Publish Date
1996
Start Page
2555
End Page
2563

Differential regulation of leucocyte L-selectin (CD62L) expression in normal lymphoid and inflamed extralymphoid tissues.

AIMS: To study tissue expression of L-selectin, a leucocyte cell surface molecule that is considered to be involved in adhesion to certain endothelia, particularly in peripheral lymph nodes and during inflammation, and is shed upon leucocyte activation. METHODS: Leucocytes were examined by immunohistochemistry and double immunofluorescence staining in various lymphoid sites and normal and inflamed extralymphoid tissues. RESULTS: L-selectin was present on mantle zone B lymphocytes in different lymphoid sites, including in intestinal lymphoid tissue, but was absent on germinal centre B cells. Splenic white pulp B cells also expressed L-selectin. The proportion of T lymphocytes expressing L-selectin depended on the site under study, being greatest in peripheral lymph nodes (mean 48% of T cells positive), and lower in mucosal lymphoid sites and spleen (9 and 11% positive, respectively). Non-lymphocytic L-selectin staining was observed on follicular dendritic cells in tonsils and on macrophages in thymus. L-selectin positive leucocytes were rare in normal extralymphoid tissues, and relatively few were seen in most inflammatory settings. However, in rejecting renal transplants, a higher proportion (30%) of leucocytes expressed L-selectin. CONCLUSIONS: Overall, the results indicate how the degree of L-selectin expression by leucocytes in particular tissues may reflect a requirement for L-selectin expression for entry into those tissues and the activation state of leucocytes once localised there.

Authors
Munro, JM; Briscoe, DM; Tedder, TF
MLA Citation
Munro, JM, Briscoe, DM, and Tedder, TF. "Differential regulation of leucocyte L-selectin (CD62L) expression in normal lymphoid and inflamed extralymphoid tissues." J Clin Pathol 49.9 (September 1996): 721-727.
PMID
9038755
Source
pubmed
Published In
Journal of Clinical Pathology
Volume
49
Issue
9
Publish Date
1996
Start Page
721
End Page
727

Lyphocyte migration in L-selectin-deficient mice. Altered subset migration and aging of the immune system.

Lymphocyte trafficking across high endothelial venules (HEV) of peripheral lymph nodes (PLN) is dependent upon lymphocyte expression of L-selectin. Mice that lack this adhesion molecule provide an opportunity to determine the long-term role of L-selectin-mediated migration in the maintenance of leukocyte subpopulations. HEV in L-selectin-deficient mice were phenotypically, morphologically, and functionally comparable with wild-type mice, although there was a 70 to 90% reduction in the number of lymphocytes within PLN. These lymphocytes most likely entered PLN through the afferent lymphatics, since they did not migrate into PLN of normal mice during short-term homing experiments. The impaired trafficking of lymphocytes across PLN-HEV resulted in the accumulation of memory (CD18highCD44high) lymphocytes within PLN, and also altered the distribution of lymphocyte subpopulations within other tissues. Specifically, a 30 to 55% increase in splenic cellularity occurred due to increases in both naive and memory lymphocytes. Circulating lymphocyte numbers or subpopulations were not altered in young L-selectin-deficient mice, but circulating monocyte numbers were increased nearly threefold. In contrast, older L-selectin-deficient mice had disproportionate increases of both naive and memory CD4+ T cells present within spleen and blood. These results and the finding that memory lymphocytes in wild-type mice expressed L-selectin demonstrate a requirement for L-selectin in the regulation of memory lymphocyte migration. Therefore, L-selectin-dependent pathways of lymphocyte migration are important for the normal migration of both naive and memory lymphocytes.

Authors
Steeber, DA; Green, NE; Sato, S; Tedder, TF
MLA Citation
Steeber, DA, Green, NE, Sato, S, and Tedder, TF. "Lyphocyte migration in L-selectin-deficient mice. Altered subset migration and aging of the immune system." J Immunol 157.3 (August 1, 1996): 1096-1106.
PMID
8757614
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
157
Issue
3
Publish Date
1996
Start Page
1096
End Page
1106

Type I (CD64) and type II (CD32) Fc gamma receptor-mediated phagocytosis by human blood dendritic cells.

Three classes of Fc receptors for IgG, Fc gamma RI (CD64), Fc gamma RII (CD32), and Fc gamma RIII (CD16), are expressed on blood leukocytes. Although Fc gamma R are important phagocytic receptors on phagocytes, most reports suggest that dendritic cells lack Fc gamma R-mediated phagocytosis and express significant levels of only CD32. We now report that phagocytically active forms of both CD64 and CD32 are expressed significantly on at least one subset of human blood dendritic cells. Countercurrent elutriation and magnetic bead selection were used to rapidly enrich subsets of blood dendritic cells (CD33brightCD14-HLA-DRbrightCD83-) and monocytes (CD33brightCD14brightHLA-DRdimCD83-). Upon culture for 2 days, dendritic cells became CD83-positive and markedly increased HLA-DR expression, whereas monocytes did not express CD83 and exhibited reduced levels of HLA-DR. Constitutive CD64 expression was identified on this circulating dendritic cell population, but at a lower level than on monocytes. CD64 expression by dendritic cells and monocytes did not decrease during 2 days in culture, and was up-regulated on both cell types following incubation with IFN-gamma. Freshly isolated blood dendritic cells performed CD64- and CD32-mediated phagocytosis, although at a lower level than monocytes. Dendritic cells generated by culture of adherent mononuclear cells in granulocyte-macrophage CSF and IL-4 also up-regulated CD64 following IFN-gamma stimulation, and mediated CD64-dependent phagocytosis. These results indicate that both CD64 and CD32 expressed on blood dendritic cells may play a role in uptake of foreign particles and macromolecules through a phagocytic mechanism before trafficking to T cell-reactive areas.

Authors
Fanger, NA; Wardwell, K; Shen, L; Tedder, TF; Guyre, PM
MLA Citation
Fanger, NA, Wardwell, K, Shen, L, Tedder, TF, and Guyre, PM. "Type I (CD64) and type II (CD32) Fc gamma receptor-mediated phagocytosis by human blood dendritic cells." J Immunol 157.2 (July 15, 1996): 541-548.
PMID
8752900
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
157
Issue
2
Publish Date
1996
Start Page
541
End Page
548

L- and P-selectins, but not CD49d (VLA-4) integrins, mediate monocyte initial attachment to TNF-alpha-activated vascular endothelium under flow in vitro.

Monocyte adhesion to the vascular endothelium is a pivotal step during their egress to tissues at sites of inflammation and immune reactions, and during atherogenesis. In this study, an in vitro flow model and blocking mAb were used to define the role of adhesion molecules in monocyte interactions with activated HUVEC under flow conditions. By videomicroscopy, freely flowing monocytes abruptly halted (initial attachment) on 6-h TNF-alpha-activated HUVEC under flow via L- and P-selectin, whereas E-selectin was not involved. CD49d/CD29 integrin (VLA-4), which can mediate initial attachment of certain T cells to VCAM-1 under flow, did not support monocyte initial attachment. Once initially attached, a small number of monocytes began rolling at 9 microns/s through a mechanism involving L-selectin, as well as CD49d and CD11/CD18 integrins, while the remaining monocytes became firmly adherent, or released to the flow stream. Monocyte stable arrest and subsequent transendothelial migration occurred rapidly and efficiently through either CD49d or CD18 integrin adhesion pathways. Transendothelial passage was also dependent on PECAM-1 (CD31). These data reveal monocytes initially attach to activated endothelium via an L-selectin-dependent mechanism, with a smaller contribution from P-selectin and no contribution by CD49d. Subsequent monocyte rolling, arrest, and transmigration require overlapping functions between multiple members of the selectin, integrin, and Ig gene families.

Authors
Luscinskas, FW; Ding, H; Tan, P; Cumming, D; Tedder, TF; Gerritsen, ME
MLA Citation
Luscinskas, FW, Ding, H, Tan, P, Cumming, D, Tedder, TF, and Gerritsen, ME. "L- and P-selectins, but not CD49d (VLA-4) integrins, mediate monocyte initial attachment to TNF-alpha-activated vascular endothelium under flow in vitro." J Immunol 157.1 (July 1, 1996): 326-335.
PMID
8683134
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
157
Issue
1
Publish Date
1996
Start Page
326
End Page
335

Engagement of the adhesion receptor CD22 triggers a potent stimulatory signal for B cells and blocking CD22/CD22L interactions impairs T-cell proliferation.

The B-lymphocyte-restricted adhesion protein CD22 mediates sialic acid-dependent cell-cell interactions. Engagement of CD22 on B lymphocytes with a CD22 monoclonal antibody (MoAb) HB22.7 that blocks the binding of CD22 to its ligand(s) directly stimulated B-cell proliferation. In addition, the HB22.7 MoAb costimulated B-cell proliferation with either anti-IgM, interleukin-2 (IL-2), IL-4, or CD40 and triggered predominantly B-cell IgG secretion with IL-2. Even more striking levels of B-cell proliferation occurred with HB22.7 MoAb under culture conditions that enhanced B-B-cell interactions. In contrast, a nonblocking CD22 MoAb (CD22.5) poorly costimulated in similar experiments. The functional differences between the two antibodies likely result from differing abilities to trigger downstream signaling events as significant differences in CD22 tyrosine phosphorylation and the recruitment of the tyrosine kinase p53/56lyn and the tyrosine phosphatase SH-PTP1C were found. Besides their role in B-cell stimulation, CD22/CD22L interactions may also assist in regulating T-cell proliferation because inhibition of CD22-CD22L engagement with the HB22.7 MoAb impaired T-cell proliferation in a costimulatory assay. Thus, CD22/CD22L interactions result in stimulatory signals for both B and T lymphocytes.

Authors
Tuscano, J; Engel, P; Tedder, TF; Kehrl, JH
MLA Citation
Tuscano, J, Engel, P, Tedder, TF, and Kehrl, JH. "Engagement of the adhesion receptor CD22 triggers a potent stimulatory signal for B cells and blocking CD22/CD22L interactions impairs T-cell proliferation." Blood 87.11 (June 1, 1996): 4723-4730.
PMID
8639842
Source
pubmed
Published In
Blood
Volume
87
Issue
11
Publish Date
1996
Start Page
4723
End Page
4730

Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22.

CD22 is a B lymphocyte-specific membrane protein that functions as an adhesion molecule via its interactions with a subset of alpha 2-6-linked sialic acid-containing glycoproteins. Engagement of CD22 with a monoclonal antibody (HB22.23) that blocks the binding of CD22 to its ligands results in rapid CD22 tyrosine phosphorylation and in increased association of CD22 with p53/56lyn kinase, p85 phosphatidyl inositol-3 kinase, and p72syk kinase. Synthetic peptides that span various regions of the intracellular portion of CD22 were used to map potential kinase binding sites. All three kinases associated with a tyrosine-phosphorylated peptide that spans tyrosine amino acid residues 822 and 842, implicating this as an important region in mediating CD22 signal transduction. In addition, purified p56lyn directly bound to the same peptide. Engagement of CD22 with HB22.23 was sufficient to stimulate normal B cell proliferation. This study further substantiates the importance of CD22 as a B lymphocyte signaling molecule and begins to unravel the mechanisms by which CD22 cross-linking can alter B cell function.

Authors
Tuscano, JM; Engel, P; Tedder, TF; Agarwal, A; Kehrl, JH
MLA Citation
Tuscano, JM, Engel, P, Tedder, TF, Agarwal, A, and Kehrl, JH. "Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22." Eur J Immunol 26.6 (June 1996): 1246-1252.
PMID
8647200
Source
pubmed
Published In
European Journal of Immunology
Volume
26
Issue
6
Publish Date
1996
Start Page
1246
End Page
1252
DOI
10.1002/eji.1830260610

CD19 is a response regulator of B lymphocyte development, activation, and differentiation.

Authors
Sato, S; Ono, N; Steeber, DA; Tedder, TF
MLA Citation
Sato, S, Ono, N, Steeber, DA, and Tedder, TF. "CD19 is a response regulator of B lymphocyte development, activation, and differentiation." FASEB JOURNAL 10.6 (April 30, 1996): 2665-2665.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
2665
End Page
2665

Lymphocyte migration and humoral immune responses in L-selectin deficient mice.

Authors
Steeber, DA; Green, NE; Sato, S; Tedder, TF
MLA Citation
Steeber, DA, Green, NE, Sato, S, and Tedder, TF. "Lymphocyte migration and humoral immune responses in L-selectin deficient mice." FASEB JOURNAL 10.6 (April 30, 1996): 173-173.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
173
End Page
173

Human blood dendritic cells express a phagocytically active form of the type-1 Fc gamma receptor (CD64).

Authors
Fanger, NA; Wardwell, K; Shen, L; Tedder, TF; Guyre, PM
MLA Citation
Fanger, NA, Wardwell, K, Shen, L, Tedder, TF, and Guyre, PM. "Human blood dendritic cells express a phagocytically active form of the type-1 Fc gamma receptor (CD64)." FASEB JOURNAL 10.6 (April 30, 1996): 2632-2632.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
2632
End Page
2632

Engagement of the adhesion receptor CD22 triggers a potent stimulatory signal for B cells and blocking CD22/CD22L interactions impairs T-cell proliferation.

Authors
Tuscano, J; Tedder, TF; Kehrl, JH
MLA Citation
Tuscano, J, Tedder, TF, and Kehrl, JH. "Engagement of the adhesion receptor CD22 triggers a potent stimulatory signal for B cells and blocking CD22/CD22L interactions impairs T-cell proliferation." FASEB JOURNAL 10.6 (April 30, 1996): 1213-1213.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
1213
End Page
1213

CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells.

Dendritic cells are potent antigen-presenting cells that initiate primary immune responses. Although dendritic cells derive from bone marrow stem cells, the intermediate stages in their development remain unknown. In this study, plastic-adherent blood monocytes (CD14+, CD1a-) cultured for 7 days with granulocyte-monocyte colony-stimulating factor, interleukin 4, and tumor necrosis factor alpha were shown to differentiate into CD1a+ CD83+ dendritic cells. These cells displayed all phenotypic and morphologic characteristics of mature dendritic cells and were the most potent stimulatory cells in allogeneic mixed leukocyte reactions. The identification of specific culture conditions that generate large numbers of dendritic cells from purified monocytes uncovers an important step in dendritic cell maturation that will allow the further characterization of their role in autoimmune diseases, graft rejection, and human immunodeficiency virus infection.

Authors
Zhou, LJ; Tedder, TF
MLA Citation
Zhou, LJ, and Tedder, TF. "CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells." Proc Natl Acad Sci U S A 93.6 (March 19, 1996): 2588-2592.
PMID
8637918
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
93
Issue
6
Publish Date
1996
Start Page
2588
End Page
2592

Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits

Leukocyte adhesion molecule (LAM) blockade reduces ischemia-reperfusion injury. We tested the hypothesis that a monoclonal antibody (MAb) that recognizes a functional epitope of L-selectin would decrease hemorrhagic shock-induced reperfusion injury. Anesthetized rabbits were subjected to 2 h of hemorrhagic shock (cardiac output reduced to 30% of baseline), then given one of the following treatments: MAbs that recognize functional domains of L- selectin (LAM1-3), CD18 (60.3), MAbs that recognize a nonfunctional domain on L-selectin (LAM1-14), or saline, immediately before resuscitation with shed blood. Additional fluids were administered as needed to maintain cardiac output at baseline levels for 6 h. The cumulative fluid resuscitation after MAb LAM1-3 (58 ± 34 ml/kg) was not significantly different from after MAb 60.3 (21 ± 24 ml/kg) or MAb LAM1-14 (66 ± 51 ml/kg), but it was significantly less than saline-treated controls (142 ± 142 ml/kg). However, two animals treated with MAb LAM1-14 died before 6 h. If their resuscitation volumes are projected to 6 h by linear regression, then the LAM1-14-treated group required significantly greater volume (101 ± 99 ml/kg) than the MAb LAM1-3-treated group. We conclude that MAbs to a functional domain on L- selectin are protective against reperfusion-injury following hemorrhagic shock.

Authors
Ramamoorthy, C; Sharar, SR; Harlan, JM; Tedder, TF; Winn, RK
MLA Citation
Ramamoorthy, C, Sharar, SR, Harlan, JM, Tedder, TF, and Winn, RK. "Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits." American Journal of Physiology - Heart and Circulatory Physiology 271.5 40-5 (1996): H1871-H1877.
Source
scival
Published In
American journal of physiology. Heart and circulatory physiology
Volume
271
Issue
5 40-5
Publish Date
1996
Start Page
H1871
End Page
H1877

Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits

Leukocyte adhesion molecule (LAM) blockade reduces ischemia-reperfusion injury. We tested the hypothesis that a monoclonal antibody (MAb) that recognizes a functional epitope of L-selectin would decrease hemorrhagic shock-induced reperfusion injury. Anesthetized rabbits were subjected to 2 h of hemorrhagic shock (cardiac output reduced to 30% of baseline), then given one of the following treatments: MAbs that recognize functional domains of L-selectin (LAM1-3), CD18 (60.3), MAbs that recognize a nonfunctional domain on L-selectin (LAM1-14), or saline, immediately before resuscitation with shed blood. Additional fluids were administered as needed to maintain cardiac output at baseline levels for 6 h. The cumulative fluid resuscitation after MAb LAM1-3 (58 ± 34 ml/kg) was not significantly different frgm after MAb 60.3 (21 ± 24 ml/kg) or MAb LAM1-14 (66 ± 51 ml/kg), but it was significantly less than saline-treated controls (142 ± 142 ml/kg). However, two animals treated with MAb LAM1-14 died before 6 h. If their resuscitation volumes are projected to 6 h by linear regression, then the LAM1-14-treated group required significantly greater volume (101 ± 99 ml/kg) than the MAb LAM1-3-treated group. We conclude that MAbs to a functional domain on L-selectin are protective against reperfusion-injury following hemorrhagic shock. Copyright © 1996 the American Physiological Society.

Authors
Ramamoorthy, C; Sharar, SR; Harlan, JM; Tedder, TP; Winn, RK
MLA Citation
Ramamoorthy, C, Sharar, SR, Harlan, JM, Tedder, TP, and Winn, RK. "Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits." American Journal of Physiology - Heart and Circulatory Physiology 40.5 (1996): H1871-H1877.
Source
scival
Published In
American journal of physiology. Heart and circulatory physiology
Volume
40
Issue
5
Publish Date
1996
Start Page
H1871
End Page
H1877

Lymphocyte Migration in L-Selectin-Deficient Mice: Altered Subset Migration and Aging of the Immune System

Lymphocyte trafficking across high endothelial venules (HEV) of peripheral lymph nodes (PLN) is dependent upon lymphocyte expression of L-selectin. Mice that lack this adhesion molecule provide an opportunity to determine the long-term role of L-selectin-mediated migration in the maintenance of leukocyte subpopulations. HEV in L-selectin-deficient mice were phenotypically, morphologically, and functionally comparable with wild-type mice, although there was a 70 to 90% reduction in the number of lymphocytes within PLN. These lymphocytes most likely entered PLN through the afferent lymphatics, since they did not migrate into PLN of normal mice during short-term homing experiments. The impaired trafficking of lymphocytes across PLN-HEV resulted in the accumulation of memory (CD18highCD44high) lymphocytes within PLN, and also altered the distribution of lymphocyte subpopulations within other tissues. Specifically, a 30 to 55% increase in splenic cellularity occurred due to increases in both naive and memory lymphocytes. Circulating lymphocyte numbers or subpopulations were not altered in young L-selectin-deficient mice, but circulating monocyte numbers were increased nearly threefold. In contrast, older L-selectin-deficient mice had disproportionate increases of both naive and memory CD4+ T cells present within spleen and blood. These results and the finding that memory lymphocytes in wild-type mice expressed L-selectin demonstrate a requirement for L-selectin in the regulation of memory lymphocyte migration. Therefore, L-selectin-dependent pathways of lymphocyte migration are important for the normal migration of both naive and memory lymphocytes.

Authors
Steeber, DA; Green, NE; Sato, S; Tedder, TF
MLA Citation
Steeber, DA, Green, NE, Sato, S, and Tedder, TF. "Lymphocyte Migration in L-Selectin-Deficient Mice: Altered Subset Migration and Aging of the Immune System." Journal of Immunology 157.3 (1996): 1096-1106.
Source
scival
Published In
Journal of Immunology
Volume
157
Issue
3
Publish Date
1996
Start Page
1096
End Page
1106

P-selectin glycoprotein ligand-1 is broadly expressed in cells of myeloid, lymphoid, and dendritic lineage and in some non-hematopoffitic cells

P-selectin glycoprotein ligand-1 (PSGL-1) is a mucin-like glycoprotein ligand for P- and E-selectin on myeloid cells and a subset of lymphocytes. We employed flow cytometry and immunohistochemistry to examine expression of PSGL-1 on minor leukocyte populations, differentiating hematppoietic cells, and non-hematopoietic tissues using two mAbs to distinct protein epitopes on PSGL-1. In the bone marrow, PSGL-1 was expressed on myeloid cells from the myeloblast stage to the segmented neutrophil, but was not detected on erythroblasts or megakaryocytes. All types of circulating myeloid cells expressed PSGL-1, and PSGL-1 was retained after extravasation of myeloid cells into tissues. PSGL-1 was also expressed on follicular dendritic cells, circulating dendritic cells, and dendritic cells in lymphoid tissue and epidermis, as well as on immature and mature thymocytes, circulating T cells, NK cells, B cells, and CD34+ progenitor cells. However, PSGL-1 expression was substantially lower on tonsillar lymphocytes than on circulating lymphocytes, suggesting that PSGL-1 was downregulated during or after entry of lymphocytes into secondary lymphoid tissue. Although PSGL-1 was detected primarily on hematopoietic cells, it was also present on the epithelium of the fallopian tube. Furthermore, PSGL-1 was detected sporadically on microvascular endothelium in some pathologic tissues. This suggests that PSGL-1 may have functions other man mediating leukocyte adhesion.

Authors
Laszik, Z; Jansen, PJ; Cummings, RD; Tedder, TF; McEver, RP; Moore, KL
MLA Citation
Laszik, Z, Jansen, PJ, Cummings, RD, Tedder, TF, McEver, RP, and Moore, KL. "P-selectin glycoprotein ligand-1 is broadly expressed in cells of myeloid, lymphoid, and dendritic lineage and in some non-hematopoffitic cells." Journal of Investigative Medicine 44.3 (1996): 329a-.
Source
scival
Published In
Journal of Investigative Medicine
Volume
44
Issue
3
Publish Date
1996
Start Page
329a

Velocity differences between L- and P-selectin-dependent neutrophil rolling in venules of mouse cremaster muscle in vivo

After surgical trauma, leukocyte rolling is initially normal in L- selectin-deficient mice and reduced at later times, whereas leukocyte rolling is initially absent in P-selectin-deficient mice but induced later. Here, we examined the possibility that P- and L-selectin support rolling at different characteristic velocities using intravital microscopy of venules of the exteriorized cremaster muscle venules of wild type (WT) and P- and L- selectin-deficient mice. At >50 min after exteriorization, rolling in P- selectin-deficient mice occurred at significantly higher velocities (129 ± 89 μm/s) than in WT mice (49 ± 23 μm/s). Rolling velocity distribution in L-selectin-deficient mice was similar to WT mice immediately after exteriorization. Histological examination of Giemsa-stained whole-mount preparations in cremaster muscle venules revealed that the majority of rolling cells (~90% in all genotypes) were granulocytes. We conclude that P- selectin mediates leukocyte rolling at velocities <50 μm/s, whereas L- selectin sustains more rapid rolling. Under physiological conditions, P- and L-selectin synergize to support rolling at velocities between 20 and 70 μm/s as seen in WT mice.

Authors
Jung, U; Bullard, DC; Tedder, TF; Ley, K
MLA Citation
Jung, U, Bullard, DC, Tedder, TF, and Ley, K. "Velocity differences between L- and P-selectin-dependent neutrophil rolling in venules of mouse cremaster muscle in vivo." American Journal of Physiology - Heart and Circulatory Physiology 271.6 40-6 (1996): H2740-H2747.
Source
scival
Published In
American journal of physiology. Heart and circulatory physiology
Volume
271
Issue
6 40-6
Publish Date
1996
Start Page
H2740
End Page
H2747

Human blood dendritic cells express a phagocytically active form of the type-1 fey receptor (CD64)

Three types of FCï receptors for IgG, FcyRI (CD64), Fc-yRII (CD32), and FcyRIII (CD16), are expressed differentially on blood leukocytes. In particular, the high affinity CD64 is constitutively expressed on mature mononuclear phagocytes of the human myeloid system. Dendritic cells (DC), in contrast, have been reported to express CD32 but not CD64. We now demonstrate that CD64 is expressed on at least one subset of blood DC. Countercurrent elutriation was used to rapidly enrich a subset of blood DC (CD33briCD14neg9HLA-DRbriCD83neg) and monocytes (CD33briCD14>iHLADRdlmCD83>9). Upon culture for two days, blood DC became CD83-positive and markedly increased HLA-DR expression, whereas monocytes did not express CD83 and exhibited reduced levels of HLA-DR. Constitutive CD64 expression was identified on this circulating DC population, but at a lower level than on monocytes. Neither DC nor monocytes demonstrated any decrease in CD64 expression following 2 days in culture. Moreover, CD64 expression on DC was upregulated following incubation with interferon-v (IFN-y), and CD64 on both freshly isolated and cultured blood DC mediated phagocytosis, although at a lower level than that of monocytes. These results indicate that both CD64 and CD32 may play a role in uptake of foreign particles and macromolecules by blood DC prior to trafficking to T cell reactive areas of the spleen.

Authors
Fanger, NA; Wardwell, K; Shen, L; Tedder, TF; Guyre, PM
MLA Citation
Fanger, NA, Wardwell, K, Shen, L, Tedder, TF, and Guyre, PM. "Human blood dendritic cells express a phagocytically active form of the type-1 fey receptor (CD64)." FASEB Journal 10.6 (1996): A1457-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
A1457

Lymphocyte migration and humoral immune responses in L-selectin deficient mice

L-selectin is involved in attachment of lymphocytes to high endochelial venules (HEV) of peripheral lymph nodes (PLN) and mediates the rolling of leukocytes upon inflamed endothelium. This study, using Lselectin deficient mice, investigated the effects of L-selectin deficiency on HEV function, the distribution of lymphocyte subpopulations and the generation of immune responses. The HEV of L-selectin deficient mice were phenotypically and functionally comparable to that of wild-type mice. In blood, L-selectin deficient mice had a 2- to 3-fold increase in the number of monocytes and a 2-fold increase in the number of CD4+ T cells with a 33% decrease in B cells. CD4+ T cells expressing a memory phenotype (CD18hi CD441) increased in both the spleen and blood of L-selectin deficient mice by 60% and 300%, respectively. L-selectin deficient mice showed elevated humoral immune responses following i.p. inoculation with either DNP-Ficoll or DNP-KLH. In contrast, the hapten-specific IgM and IgG responses were decreased by 40% and 92%, respectively, in Lselectin deficient mice following footpad immunization with DNP-KLH. Following a secondary inoculation of DNP-KLH, the L-selectin deficient mice mounted an increased humoral response regardless of the route of inoculation. Thus, the lack of L-selectin results in a marked redistribution of lymphocyte subsets including the accumulation of memory cells within lymphoid tissues. While L-selectin is not required for the generation of humoral immune responses, it does facilitate a more rapid primary immune response to peripheral antigenic challenge.

Authors
Steeber, DA; Green, NE; Sato, S; Tedder, TP
MLA Citation
Steeber, DA, Green, NE, Sato, S, and Tedder, TP. "Lymphocyte migration and humoral immune responses in L-selectin deficient mice." FASEB Journal 10.6 (1996): A1029-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
A1029

Engagement of the adhesion receptor cd22 triggers a potent stimulatory signal for b cells and blocking cd22/cd22l interactions impairs t-cell proliferation

The B lymphocyte-restricted adhesion protein CD22 mediates sialic aciddependent cell-cell interactions. Engagement of CD22 on B lymphocytes with a CD22 mAb HB22.7 that blocks the binding of CD22 to its ligand(s) directly stimulated B-cell proliferation. In addition, the HB22.7 mAb co-stimulated B cell proliferation with either anti-lgM, interleukin (ID-2, IL-4, or CD40 and triggered predominantly B cell IgG secretion with IL-2. Even more striking levels of B cell proliferation occurred with HB22.7 mAb under culture conditions that enhanced B-B cell interactions. In contrast, a non-blocking CD22 mAb (CD22.5) poorly co-stimulated in similar experiments. The functional differences between the two antibodies likely result from differing abilities to trigger downstream signaling events as significant differences in CD22 tyrosine phosphorylation and the recruitment of the tyrosine kinase p53/56lyn and the tyrosine phosphatase SH-PTP1C were found. Besides their role in B cell stimulation, CD22/CD22L interactions may also assist in regulating T-cell proliferation because inhibition of CD22-CD22L engagement with the HB22.7 mAb impaired T cell proliferation in a co-stimulatory assay. Thus, CD22/CD22L interactions result in stimulatory signals for both B and T lymphocytes.

Authors
Tuscano, J; Tedder, TF; Kehrl, JH
MLA Citation
Tuscano, J, Tedder, TF, and Kehrl, JH. "Engagement of the adhesion receptor cd22 triggers a potent stimulatory signal for b cells and blocking cd22/cd22l interactions impairs t-cell proliferation." FASEB Journal 10.6 (1996): A1209-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
A1209

CD19 is a response regulator of B lymphocyte development, activation, and differentiation

CD19-deficient mice generate normal numbers of bone marrow B cells, but have decreased numbers of peripheral B cells with a dramatic loss within the Bl lineage. In contrast, transgenic mice that express human CD19 (hCD19) suggests a role for CD19 in early B cell clonal deletion since there is a significant decrease in the number of B cells generated within the bone marrow. CD19-deficient B cells are hyporesponsive to mitogenic stimulation and have decreased serum Ig levels while transgenic mice that overexpress CD19 are hyperresponsive. The role of CD19 in B cell growth regulation in vivo was examined further by generating mice expressing various densities of cell surface CD 19. Mice that expressed wild-type levels of hCD19 in the absence of endogenous mouse CD19 showed normal B cell development and function, including Bl cells. These mice also demonstrated normal serum Ig levels. In contrast, mice that overexpressed CD19 (2-3 fold) had significant defects in early B cell development of conventional B cells, dramatically increased numbers of Bl cells, augmented mitogenic responses and increased serum Ig levels. Thus, hCD19 can functionally replace mouse CD 19. In addition, slight changes in CD 19 receptor density dramatically affected B cell development as the number of B-l cells, proliferative responses, and serum Ig levels correlated with the surface expression levels of CD 19. These experiments suggest that CD 19 functions to define signaling thresholds for cell surface receptors that regulate B lymphocyte selection, activation and differentiation.

Authors
Sato, S; Ono, N; Steeher, DA; Tedder, TF
MLA Citation
Sato, S, Ono, N, Steeher, DA, and Tedder, TF. "CD19 is a response regulator of B lymphocyte development, activation, and differentiation." FASEB Journal 10.6 (1996): A1462-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
A1462

The CD19 signal transduction molecule is a response regulator of B-lymphocyte differentiation.

The phenotypes of CD19-deficient (CD19-/-) mice, and human CD19-transgenic (hCD19TG) mice that overexpress CD19 indicate that CD19 is a response regulator of B-lymphocyte surface receptor signaling. To further characterize the function of CD19 during B-cell differentiation, humoral immune responses to a T-cell-independent type 1 [trinitrophenyl-lipopolysaccharide (TNP-LPS)], a T-cell-independent type 2 [dinitrophenyl (DNP)-Ficoll], and a T-cell-dependent [DNP-keyhole limpet hemocyanin (KLH)] antigen were assessed in CD19-/- and hCD19TG mice. B cells from CD19-/- mice differentiated and underwent immunoglobulin isotype switching in vitro in response to mitogens and cytokines. In vivo, CD19-/- mice generated humoral responses to TNP-LPS and DNP-KLH that were dramatically lower than those of wild-type littermates. Surprisingly, the humoral response to DNP-Ficoll was significantly greater in CD19-/- mice. In contrast, hCD19TG mice were hyperresponsive to TNP-LPS and DNP-KLH immunization but were hyporesponsive to DNP-Ficoll. These results demonstrate that CD19 is not required for B-cell differentiation and isotype switching but serves as a response regulator which modulates B-cell differentiation. Since humoral responses to both T-cell-dependent and T-cell-independent antigens were similarly affected by alterations in CD19 expression, these differences are most likely to result from intrinsic changes in B-cell function rather than from the selective disruption of B-cell interactions with T cells.

Authors
Sato, S; Steeber, DA; Tedder, TF
MLA Citation
Sato, S, Steeber, DA, and Tedder, TF. "The CD19 signal transduction molecule is a response regulator of B-lymphocyte differentiation." Proc Natl Acad Sci U S A 92.25 (December 5, 1995): 11558-11562.
PMID
8524803
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
92
Issue
25
Publish Date
1995
Start Page
11558
End Page
11562

Structure of the mouse CD83 gene

Authors
Twist, CJ; Disteche, C; Beier, D; Tedder, TF
MLA Citation
Twist, CJ, Disteche, C, Beier, D, and Tedder, TF. "Structure of the mouse CD83 gene." BLOOD 86.10 (November 15, 1995): 1280-1280.
Source
wos-lite
Published In
Blood
Volume
86
Issue
10
Publish Date
1995
Start Page
1280
End Page
1280

A distinct pattern of cytokine gene expression by human CD83+ blood dendritic cells.

Dendritic cells are the most potent antigen-presenting cells of the immune system. Although dendritic cells are likely to secrete selective cytokines that facilitate antigen presentation, the difficulty in isolating pure dendritic cells in sufficient numbers has made assessment of this function imprecise. In this study, pure populations of CD83+ human blood dendritic cells were isolated by previously established enrichment procedures and subsequent cell sorting. Cytokine gene expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR) amplification of mRNA. Resting CD83+ dendritic cells expressed interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta 1 (TGF-beta 1) mRNA, while activation of cells with phorbol myristate acetate induced IL-1 alpha and beta, IL-9, TNF-beta, interferon-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), M-CSF, and G-CSF mRNA expression. Resting CD83+ cells also expressed the Rantes, MCP-1, MIP-1 alpha, and MIP-1 beta chemokines, with 1-309 expression induced upon activation. Resting and activated CD83+ dendritic cells also expressed receptors for IL-2 (CD25), TGF-beta 1 and -beta 3, and GM-CSF as determined by indirect immunofluorescence staining. These results indicate that dendritic cells have the ability to produce a variety of soluble factors which are likely to contribute substantially to the potent allostimulatory activity of these cells.

Authors
Zhou, LJ; Tedder, TF
MLA Citation
Zhou, LJ, and Tedder, TF. "A distinct pattern of cytokine gene expression by human CD83+ blood dendritic cells." Blood 86.9 (November 1, 1995): 3295-3301.
PMID
7579430
Source
pubmed
Published In
Blood
Volume
86
Issue
9
Publish Date
1995
Start Page
3295
End Page
3301

Alterations in soluble and leukocyte surface L-selectin (CD 62L) in hemodialysis patients.

Hemodialysis (HD) patients can develop acute reactions during treatment as well as increased long-term susceptibility to infections and malignancy. Leukocyte-membrane interactions may contribute to these processes. The effects of a single HD session on L-selectin, a leukocyte adhesion molecule for endothelium, were examined. Serum levels of soluble L-selectin were measured in 23 patients by enzyme-linked immunosorbent assay before and after a 3-h dialysis session. There was a statistically significant increase in soluble L-selectin from 1.36 +/- 0.12 (SE) to 1.57 +/- 0.18 micrograms/mL (P < 0.001). An increase in shed L-selectin was observed for the "venous" compared with the "arterial" part of the dialyser (P < 0.01) 15 min into HD. Soluble L-selectin levels were found to remain increased at 3 h after treatment. Leukocyte-bound L-selectin and CD11b was examined by the use of flow cytometry. Neutrophil L-selectin decreased to 69 +/- 7% at 15 min (P < 0.01) and then rebounded to 98 +/- 7% at 180 min. Monocyte and lymphocyte L-selectin did not decrease. Because L-selectin is important for leukocyte attachment to endothelium at sites of inflammation, alterations of shed L-selectin and cell-surface L-selectin levels may play a role in the immunologic consequences of HD treatment.

Authors
Rabb, H; Agosti, SJ; Bittle, PA; Fernandez, M; Ramirez, G; Tedder, TF
MLA Citation
Rabb, H, Agosti, SJ, Bittle, PA, Fernandez, M, Ramirez, G, and Tedder, TF. "Alterations in soluble and leukocyte surface L-selectin (CD 62L) in hemodialysis patients." J Am Soc Nephrol 6.5 (November 1995): 1445-1450.
PMID
8589321
Source
pubmed
Published In
Journal of the American Society of Nephrology : JASN
Volume
6
Issue
5
Publish Date
1995
Start Page
1445
End Page
1450

Structural requirements regulate endoproteolytic release of the L-selectin (CD62L) adhesion receptor from the cell surface of leukocytes.

L-selectin mediates leukocyte rolling on vascular endothelium at sites of inflammation and lymphocyte migration to peripheral lymph nodes. L-selectin is rapidly shed from the cell surface after leukocyte activation by a proteolytic mechanism that cleaves the receptor in a membrane proximal extracellular region. This process may allow rapid leukocyte detachment from the endothelial surface before entry into tissues. In this study, the structural requirements for regulation of human L-selectin endoproteolytic release were examined through analysis of chimeric selectin molecules and mutant L-selectin receptors. The use of chimeric selectins and a cytoplasmic tail truncation mutant demonstrated that the extracellular membrane-proximal 15-amino acid region of L-selectin is required for endoproteolytic release. The introduction of alanine-scanning mutations within this membrane-proximal region did not prevent endoproteolytic release, indicating that a specific amino acid motif was not an absolute requirement for cleavage. Furthermore, alterations within the putative primary cleavage site (K283-S284) resulted in either constitutive endoproteolytic release of the receptor or inhibition of cell activation-induced shedding to variable extents. The length of the membrane-proximal region was also critical since truncations of this region completely abolished endoproteolytic release. Thus, release of L-selectin is likely to be regulated by the generation of an appropriate tertiary conformation within the membrane-proximal region of the receptor which allows recognition by a membrane-bound endoprotease with relaxed sequence specificity that cleaves the receptor at a specific distance from the plasma membrane. These observations suggest a generalized protein-processing pathway involved in the endoproteolytic release of specific transmembrane proteins which harbor widely differing primary sequences at or neighboring their cleavage sites.

Authors
Chen, A; Engel, P; Tedder, TF
MLA Citation
Chen, A, Engel, P, and Tedder, TF. "Structural requirements regulate endoproteolytic release of the L-selectin (CD62L) adhesion receptor from the cell surface of leukocytes." J Exp Med 182.2 (August 1, 1995): 519-530.
PMID
7543141
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
182
Issue
2
Publish Date
1995
Start Page
519
End Page
530

Leukocyte interactions with vascular endothelium. New insights into selectin-mediated attachment and rolling.

Among the earliest signs of inflammation is the capture of leukocytes from the blood stream and their subsequent rolling along the endothelium of postcapillary venules. This commentary summarizes recent insight into the molecular basis of leukocyte rolling gained from gene-targeted mice, Ab blocking studies, and in vitro and in vivo reconstitution assays. These data reveal how the selectins individually and collectively contribute to the process of leukocyte capture and subsequent rolling on vascular endothelium.

Authors
Ley, K; Tedder, TF
MLA Citation
Ley, K, and Tedder, TF. "Leukocyte interactions with vascular endothelium. New insights into selectin-mediated attachment and rolling." J Immunol 155.2 (July 15, 1995): 525-528.
PMID
7541818
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
155
Issue
2
Publish Date
1995
Start Page
525
End Page
528

Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule.

CD19-deficient mice were generated to examine the role of CD19 in B cell growth regulation in vivo. Deletion of CD19 had no deleterious effects on the generation of B cells in the bone marrow, but there was a significant reduction in the number of B cells in peripheral lymphoid tissues. B cells from CD19-deficient mice exhibited markedly decreased proliferative responses to mitogens, and serum immunoglobulin levels were also significantly decreased. In contrast, mice that overexpressed CD19 had significant defects in early B cell development in the bone marrow, augmented mitogenic responses, and increased serum immunoglobulin levels. These experiments indicate that CD19 functions to define signaling thresholds for cell surface receptors that regulate B lymphocyte selection, activation, and differentiation.

Authors
Engel, P; Zhou, LJ; Ord, DC; Sato, S; Koller, B; Tedder, TF
MLA Citation
Engel, P, Zhou, LJ, Ord, DC, Sato, S, Koller, B, and Tedder, TF. "Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule." Immunity 3.1 (July 1995): 39-50.
PMID
7542548
Source
pubmed
Published In
Immunity
Volume
3
Issue
1
Publish Date
1995
Start Page
39
End Page
50

The selectins: vascular adhesion molecules.

The selectin family of adhesion molecules mediates the initial attachment of leukocytes to venular endothelial cells before their firm adhesion and diapedesis at sites of tissue injury and inflammation. The selectin family consists of three closely related cell-surface molecules with differential expression by leukocytes (L-selectin), platelets (P-selectin), and vascular endothelium (E- and P-selectin). The selectins have characteristic extracellular regions composed of an amino-terminal lectin domain that binds a carbohydrate ligand, an epidermal growth factor-like domain, and two to nine short repeat units homologous to domains found in complement binding proteins. In contrast to most other adhesion molecules, selectin function is restricted to leukocyte interactions with vascular endothelium. Multiple studies indicate that the selectins mediate neutrophil, monocyte, and lymphocyte rolling along the venular wall. The generation of selectin-deficient mice has confirmed these findings and provided further insight into how the overlapping functions of these receptors regulate inflammatory processes. Selectin-directed therapeutic agents are now proven to be effective in blocking many of the pathological effects resulting from leukocyte entry into sites of inflammation. Future studies are focused on how the selectins interact with the increasing array of other adhesion molecules and inflammatory mediators.

Authors
Tedder, TF; Steeber, DA; Chen, A; Engel, P
MLA Citation
Tedder, TF, Steeber, DA, Chen, A, and Engel, P. "The selectins: vascular adhesion molecules." FASEB J 9.10 (July 1995): 866-873. (Review)
PMID
7542213
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
9
Issue
10
Publish Date
1995
Start Page
866
End Page
873

L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites.

L-selectin, a cell surface adhesion molecule that is expressed by most leukocytes, mediates leukocyte rolling along vascular endothelium at sites of inflammation. The contribution of L-selectin to leukocyte migration in models of chronic inflammation was assessed by using mice that lack cell surface L-selectin expression. Significant inhibition of neutrophil (56-62%), lymphocyte (70-75%), and monocyte (72-78%) migration into an inflamed peritoneum was observed 24 and 48 h after administration of thioglycollate, an inflammatory stimulus. L-selectin-deficient mice were also significantly impaired in delayed-type hypersensitivity reactions. Footpad swelling in response to sheep red blood cell challenge was reduced 75% in L-selectin-deficient mice compared with wild-type mice. Ear swelling in a model of contact hypersensitivity induced by oxazolone challenge was also reduced by 69% compared to wild-type mice. Consistent with L-selectin-mediating leukocyte migration into diverse vascular beds during inflammation, L-selectin-deficient mice were significantly resistant to death resulting from lipopolysaccharide (LPS)-induced toxic shock. LPS administration resulted in a 90% mortality rate in control mice after 24 h, while there was a 90% survival rate in L-selectin-deficient mice. These results demonstrate that L-selectin plays a prominent role in leukocyte homing to nonlymphoid tissues during inflammation and that blocking this process can be beneficial during pathological inflammatory responses.

Authors
Tedder, TF; Steeber, DA; Pizcueta, P
MLA Citation
Tedder, TF, Steeber, DA, and Pizcueta, P. "L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites." J Exp Med 181.6 (June 1, 1995): 2259-2264.
PMID
7539045
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
181
Issue
6
Publish Date
1995
Start Page
2259
End Page
2264

Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily.

Dendritic cells are potent APC that initiate primary T cell-dependent immune responses. The lack of lineage-associated cell surface Ags for human dendritic cells has made characterization of this lineage difficult. In this study, analysis of leukocyte subpopulations isolated from human blood revealed that circulating or cultured B and T cells, NK cells, and monocytes did not express CD83, whereas CD83+ cells were predominantly found in the dendritic cell-enriched metrizamide low density fraction of plastic nonadherent blood mononuclear cells. Blood CD83+ cells had a cellular morphology characteristic of dendritic cells and a cell surface phenotype that did not correlate with that of T cells, B cells, NK cells, or cells of the myelomonocytic lineage. Analysis of CD83+ cells with a panel of mAbs that identify 126 leukocyte cell surface Ags revealed the CD83+ cells to be a phenotypically homogeneous and unique population of cells that expressed the highest levels of MHC class II molecules when compared with other leukocyte lineages. CD83+ cells were also the most potent stimulator cells in an allogeneic MLR when compared with other leukocyte lineages. Functional analysis of CD83+ cells revealed that MHC class II, CD11a, CD40 and CD86 played functionally dominant roles, whereas CD80 contributed minimally to the specialized costimulatory activity of these potent APC. Thus, CD83 serves as a useful and specific marker for this unique population of human blood dendritic cells.

Authors
Zhou, LJ; Tedder, TF
MLA Citation
Zhou, LJ, and Tedder, TF. "Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily." J Immunol 154.8 (April 15, 1995): 3821-3835.
PMID
7706722
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
154
Issue
8
Publish Date
1995
Start Page
3821
End Page
3835

Identification of the ligand-binding domains of CD22, a member of the immunoglobulin superfamily that uniquely binds a sialic acid-dependent ligand.

CD22 is a B cell-restricted member of the immunoglobulin (Ig) superfamily that functions as an adhesion receptor for leukocytes and erythrocytes. CD22 is unique among members of the Ig superfamily in that it has been suggested to bind a series of sialic acid-dependent ligands, potentially through different functional domains expressed by different splice variants of CD22. In this study, the epitopes identified by a large panel of function-blocking and non-function-blocking CD22 monoclonal antibodies were localized to specific Ig-like domains, revealing that all function-blocking monoclonal antibodies bound to the first and/or second Ig-like domains. Consistent with a single ligand-binding region, the two amino-terminal domains were the functional unit that mediated CD22 adhesion with lymphocytes, neutrophils, monocytes, and erythrocytes. The predominant cell surface species of CD22 was a full length 140,000 relative molecular mass seven Ig-like domain glycoprotein and a minor 130,000 relative molecular mass form lacking the fourth domain. While the two amino-terminal Ig-like domains of CD22 are structurally similar to those found in other members of the Ig superfamily involved in cell adhesion and containing an amino acid sequence motif associated with integrin recognition, site-directed mutagenesis of critical residues surrounding this motif did not disrupt CD22-mediated adhesion. These results demonstrate that the unique ligand-binding properties of CD22 are distinct from those of other members of the Ig superfamily involved in integrin-mediated cell adhesion.

Authors
Engel, P; Wagner, N; Miller, AS; Tedder, TF
MLA Citation
Engel, P, Wagner, N, Miller, AS, and Tedder, TF. "Identification of the ligand-binding domains of CD22, a member of the immunoglobulin superfamily that uniquely binds a sialic acid-dependent ligand." J Exp Med 181.4 (April 1, 1995): 1581-1586.
PMID
7535343
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
181
Issue
4
Publish Date
1995
Start Page
1581
End Page
1586

PHENOTYPE AND FUNCTIONAL-PROPERTIES OF HUMAN BLOOD DENDRITIC CELLS THAT SELECTIVELY EXPRESS CD83

Authors
TEDDER, TF
MLA Citation
TEDDER, TF. "PHENOTYPE AND FUNCTIONAL-PROPERTIES OF HUMAN BLOOD DENDRITIC CELLS THAT SELECTIVELY EXPRESS CD83." JOURNAL OF CELLULAR BIOCHEMISTRY (March 10, 1995): 32-32.
Source
wos-lite
Published In
Journal of Cellular Biochemistry
Publish Date
1995
Start Page
32
End Page
32

L-SELECTIN AND P-SELECTIN PREFERENTIALLY MEDIATE MONOCYTE INITIAL ATTACHMENT AND ROLLING ON TNF-ACTIVATED ENDOTHELIUM UNDER FLOW CONDITIONS IN-VITRO

Authors
LUSCINSKAS, FW; DING, H; TAN, P; TEDDER, TF; GERRITSEN, ME
MLA Citation
LUSCINSKAS, FW, DING, H, TAN, P, TEDDER, TF, and GERRITSEN, ME. "L-SELECTIN AND P-SELECTIN PREFERENTIALLY MEDIATE MONOCYTE INITIAL ATTACHMENT AND ROLLING ON TNF-ACTIVATED ENDOTHELIUM UNDER FLOW CONDITIONS IN-VITRO." FASEB JOURNAL 9.3 (March 9, 1995): A269-A269.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
9
Issue
3
Publish Date
1995
Start Page
A269
End Page
A269

Sequential contribution of L- and P-selectin to leukocyte rolling in vivo.

Leukocyte recruitment into inflammatory sites is initiated by a reversible transient adhesive contact with the endothelium called leukocyte rolling, which is thought to be mediated by the selectin family of adhesion molecules. Selectin-mediated rolling precedes inflammatory cell emigration, which is significantly impaired in both P- and L-selectin gene-deficient mice. We report here that approximately 13% of all leukocytes passing venules of the cremaster muscle of wild-type mice roll along the endothelium at < 20 min after surgical dissection. Rolling leukocyte flux fraction reaches a maximum of 28% at 40-60 min and returns to 13% at 80-120 min. In P-selectin-deficient mice, rolling is absent initially and reaches 5% at 80-120 min. Rolling flux fraction in L-selectin-deficient mice is similar to wild type initially and declines to 5% at 80-120 min. In both wild-type and L-selectin-deficient mice, initial leukocyte rolling (0-60 min) is completely blocked by the P-selectin monoclonal antibody (mAb) RB40.34, but unaffected by L-selectin mAb MEL-14. Conversely, rolling at later time points (60-120 min) is inhibited by mAb MEL-14 but not by mAb RB40.34. After treatment with tumor necrosis factor (TNF)-alpha for 2 h, approximately 24% of all passing leukocytes roll in cremaster venules of wild-type and P-selectin gene-deficient mice. Rolling in TNF-alpha-treated mice is unaffected by P-selectin mAb or E-selectin mAb 10E9.6. By contrast, rolling in TNF-alpha-treated P-selectin-deficient mice is completely blocked by L-selectin mAb. These data show that P-selectin is important during the initial induction of leukocyte rolling after tissue trauma. At later time points and in TNF-alpha-treated preparations, rolling is largely L-selectin dependent. Under the conditions tested, we are unable to find evidence for involvement of E-selectin in leukocyte rolling in mice.

Authors
Ley, K; Bullard, DC; Arbonés, ML; Bosse, R; Vestweber, D; Tedder, TF; Beaudet, AL
MLA Citation
Ley, K, Bullard, DC, Arbonés, ML, Bosse, R, Vestweber, D, Tedder, TF, and Beaudet, AL. "Sequential contribution of L- and P-selectin to leukocyte rolling in vivo." J Exp Med 181.2 (February 1, 1995): 669-675.
PMID
7530761
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
181
Issue
2
Publish Date
1995
Start Page
669
End Page
675

Three populations of cells with dendritic morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type 1.

Conflicting data have been reported with regard to the infectability, dysfunction, and depletion of dendritic cells (DCs) in human immunodeficiency virus (HIV) disease. These discrepancies could potentially be explained by the existence of multiple subsets of cells with dendritic morphology in peripheral blood. The isolation of DCs in humans is accomplished through negative selection until a morphologically pure population is obtained. Recently, DC precursors purified from peripheral blood by negative selection have been observed to develop into functionally and morphologically mature DCs. In this report we identify three populations of cells in peripheral blood that have or can develop a dendritic morphology. The first population, when allowed to mature in culture, develops a dendritic morphology and gains the expression of HB15, a marker of DCs in blood, thymus, skin, and lymphoid organs. The second population expresses HB15 and has the phenotypic and morphologic characteristics of mature DCs. The third population is morphologically very similar to mature DCs but does not share the same T-cell-stimulatory activity and is the only population that is infectable with HIV. Understanding the heterogeneity of cells of dendritic lineage and/or morphology in the peripheral blood will aid in understanding their role as antigen-presenting cells in general and as potential participants in the immunopathogenesis of HIV disease.

Authors
Weissman, D; Li, Y; Ananworanich, J; Zhou, LJ; Adelsberger, J; Tedder, TF; Baseler, M; Fauci, AS
MLA Citation
Weissman, D, Li, Y, Ananworanich, J, Zhou, LJ, Adelsberger, J, Tedder, TF, Baseler, M, and Fauci, AS. "Three populations of cells with dendritic morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type 1." Proc Natl Acad Sci U S A 92.3 (January 31, 1995): 826-830.
PMID
7846060
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
92
Issue
3
Publish Date
1995
Start Page
826
End Page
830

Lectin and epidermal growth factor domains of P-selectin at physiologic density are the recognition unit for leukocyte binding.

P-selectin is an integral membrane glycoprotein on stimulated platelets and endothelial cells that serves as a receptor for leukocytes. To estimate the density of P-selectin in membranes necessary to support adhesion, we incorporated purified P-selectin at varying concentrations into phospholipid bilayers that encapsulated glass microspheres. Maximal binding of these lipospheres to HL60 cells, a P-selectin ligand-expressing cell line, was approached at a P-selectin density of about 100 molecules per microns 2; half-maximal binding was observed at about 50 to 60 molecules per microns 2. Compatible results were obtained with P-selectin expressed on Chinese hamster ovary cells. The P-selectin density on stimulated platelets was estimated to be 150 to 200 molecules/microns 2. To identify the domains of P-selectin required for HL60 cell binding, chimeras of P-selectin and L-selectin were stably expressed in Chinese hamster ovary cells and clones that expressed the chimeras at the estimated physiologic density were selected. Chimeras containing the P-selectin lectin and epidermal growth factor (EGF) domains or the lectin, EGF, and short consensus repeats bound HL60 cells equivalently, but a chimera containing the P-selectin lectin domain alone bound HL60 cells much less well. These results indicate that at a physiologically relevant P-selectin density on membrane surfaces, the lectin, and EGF domains of P-selectin are together required for optimal leukocyte binding.

Authors
Gibson, RM; Kansas, GS; Tedder, TF; Furie, B; Furie, BC
MLA Citation
Gibson, RM, Kansas, GS, Tedder, TF, Furie, B, and Furie, BC. "Lectin and epidermal growth factor domains of P-selectin at physiologic density are the recognition unit for leukocyte binding." Blood 85.1 (January 1, 1995): 151-158.
PMID
7528563
Source
pubmed
Published In
Blood
Volume
85
Issue
1
Publish Date
1995
Start Page
151
End Page
158

Review of the B cell section of the Fifth International Workshop on Human Leukocyte Differentiation Antigens

Authors
Tedder, TF; Engel, P
MLA Citation
Tedder, TF, and Engel, P. "Review of the B cell section of the Fifth International Workshop on Human Leukocyte Differentiation Antigens." Clinical Immunology Newsletter 15.1 (1995): 6-8.
Source
scival
Published In
Clinical Immunology Newsletter
Volume
15
Issue
1
Publish Date
1995
Start Page
6
End Page
8

Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily

Dendritic cells are potent APC that initiate primary T cell-dependent immune responses. The lack of lineage-associated cell surface Ags for human dendritic cells has made characterization of this lineage difficult. In this study, analysis of leukocyte subpopulations isolated from human blood revealed that circulating or cultured B and T cells, NK cells, and monocytes did not express CD83, whereas CD83+ cells were predominantly found in the dendritic cell-enriched metrizamide low density fraction of plastic nonadherent blood mononuclear cells. Blood CD83+ cells had a cellular morphology characteristic of dendritic cells and a cell surface phenotype that did not correlate with that of T cells, B cells, NK cells, or cells of the myelomonocytic lineage. Analysis of CD83+ cells with a panel of mAbs that identify 126 leukocyte cell surface Ags revealed the CD83+ cells to be a phenotypically homogeneous and unique population of cells that expressed the highest levels of MHC class II molecules when compared with other leukocyte lineages. CD83+ cells were also the most potent stimulator cells in an allogeneic MLR when compared with other leukocyte lineages. Functional analysis of CD83+ cells revealed that MHC class II, CD11a, CD40 and CD86 played functionally dominant roles, whereas CD80 contributed minimally to the specialized costimulatory activity of these potent APC. Thus, CD83 serves as a useful and specific marker for this unique population of human blood dendritic cells. Copyright © 1995 by The American Association of Immunologists.

Authors
Zhou, L-J; Tedder, TF
MLA Citation
Zhou, L-J, and Tedder, TF. "Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily." Journal of Immunology 154.8 (1995): 3836-3842.
Source
scival
Published In
Journal of Immunology
Volume
154
Issue
8
Publish Date
1995
Start Page
3836
End Page
3842

CD antigens 1993: An updated nomenclature for clusters of differentiation on human cells

Authors
Schlossman, SF; Boumsell, L; Gilks, W; Harlan, JM; Kishimoto, T; Morimoto, C; Ritz, J; Shaw, S; Silverstein, RL; Springer, TA; Tedder, TF; Tood, RF
MLA Citation
Schlossman, SF, Boumsell, L, Gilks, W, Harlan, JM, Kishimoto, T, Morimoto, C, Ritz, J, Shaw, S, Silverstein, RL, Springer, TA, Tedder, TF, and Tood, RF. "CD antigens 1993: An updated nomenclature for clusters of differentiation on human cells." Revista Espanola de Alergologia e Inmunologia Clinica 10.4 (1995): 199-200.
Source
scival
Published In
Revista Espanola de Alergologia e Inmunologia Clinica
Volume
10
Issue
4
Publish Date
1995
Start Page
199
End Page
200

L-SELECTIN REGULATION OF LYMPHOCYTE HOMING AND LEUKOCYTE ROLLING AND MIGRATION

Authors
TEDDER, TF; CHEN, AJ; ENGEL, P
MLA Citation
TEDDER, TF, CHEN, AJ, and ENGEL, P. "L-SELECTIN REGULATION OF LYMPHOCYTE HOMING AND LEUKOCYTE ROLLING AND MIGRATION." 1995.
Source
wos-lite
Published In
CARDIOVASCULAR DISEASE 2
Publish Date
1995
Start Page
173
End Page
184

Inhibition of leukocyte L-selectin function with a monoclonal antibody attenuates reperfusion injury to the rabbit ear.

The leukocyte adhesion molecule L-selectin mediates neutrophil adhesive interactions with endothelial cells and is in part responsible for neutrophil rolling. We examined the role of L-selectin in ischemia-reperfusion injury of rabbit ears using a monoclonal antibody (MoAb) directed to a functional epitope of L-selectin. Arterial blood flow to the rabbit ear was occluded for six hours with ambient temperature at 23 degrees C to 24 degrees C. Rabbits were treated at reperfusion with saline (n = 8), the L-selectin function-blocking LAM1-3 MoAb (2 mg/kg), or the nonfunction-blocking LAM1-14 MoAb (2 mg/kg). Tissue injury was determined by measuring edema and necrosis. Edema in the LAM1-3 MoAb-treated group (peak = 25 +/- 4 mL) was significantly less (P < .05) than in saline-treated (peak = 40 +/- 8 mL) and LAM1-14 MoAb-treated (peak = 41 +/- 6 mL) groups. Tissue necrosis at 7 days was not observed in the LAM1-3 MoAb-treated group, whereas significant necrosis (P < .05) was seen in the saline- (8% +/- 3% necrosis) and LAM1-14 MoAb-treated (7% +/- 3% necrosis) group. We conclude that blocking L-selectin ameliorates necrosis and edema after ischemia and reperfusion in the rabbit ear, presumably by blocking neutrophil rolling.

Authors
Mihelcic, D; Schleiffenbaum, B; Tedder, TF; Sharar, SR; Harlan, JM; Winn, RK
MLA Citation
Mihelcic, D, Schleiffenbaum, B, Tedder, TF, Sharar, SR, Harlan, JM, and Winn, RK. "Inhibition of leukocyte L-selectin function with a monoclonal antibody attenuates reperfusion injury to the rabbit ear." Blood 84.7 (October 1, 1994): 2322-2328.
PMID
7522626
Source
pubmed
Published In
Blood
Volume
84
Issue
7
Publish Date
1994
Start Page
2322
End Page
2328

The B7-2 (B70) costimulatory molecule expressed by monocytes and activated B lymphocytes is the CD86 differentiation antigen.

T-cell activation is initiated after T-cell receptor binding to antigen, but also requires interactions between costimulatory molecules expressed on antigen-presenting cells. An important costimulatory molecule expressed by monocytes and activated B lymphocytes has been recently identified and termed B7-2 or B70. Independently, a new Cluster of Differentiation was defined in the Fifth International Leukocyte Differentiation Antigen Workshop as CD86, a molecule predominantly expressed by monocytes and activated B lymphocytes. In this study, the two monoclonal antibodies that defined CD86, FUN-1 and BU-63, were shown to bind to cDNA transfected cells expressing B7-2/B70. The FUN-1 monoclonal antibody also completely blocked the costimulatory activity of B7-2/B70 in functional assays. Therefore, the serologically defined CD86 differentiation antigen is the B7-2/B70 molecule.

Authors
Engel, P; Gribben, JG; Freeman, GJ; Zhou, LJ; Nozawa, Y; Abe, M; Nadler, LM; Wakasa, H; Tedder, TF
MLA Citation
Engel, P, Gribben, JG, Freeman, GJ, Zhou, LJ, Nozawa, Y, Abe, M, Nadler, LM, Wakasa, H, and Tedder, TF. "The B7-2 (B70) costimulatory molecule expressed by monocytes and activated B lymphocytes is the CD86 differentiation antigen." Blood 84.5 (September 1, 1994): 1402-1407.
PMID
7520767
Source
pubmed
Published In
Blood
Volume
84
Issue
5
Publish Date
1994
Start Page
1402
End Page
1407

Comparison of human eosinophil and neutrophil adhesion to endothelial cells under nonstatic conditions. Role of L-selectin.

To simulate adhesion that occurs under conditions of flow, we investigated the attachment of eosinophils to endothelium under rotational conditions. Tissue-culture plates containing monolayers of HUVEC were placed on a horizontal rotator (80 revolutions per minute (rpm)), and equal numbers of purified human eosinophils or neutrophils were added to separate wells at 4 degrees C. Binding of eosinophils and neutrophils to unstimulated endothelial cells was 15 +/- 3 and 31 +/- 11 cells/four high power fields (HPF), respectively. After preincubation of HUVEC with IL-1 beta (1 ng/ml, 4 h, 37 degrees C), adhesion increased to 56 +/- 4 and 290 +/- 26 cells/four HPF, respectively (p < 0.0002 for both, n = 8-14). Eosinophils with reduced levels of L-selectin (blood eosinophils activated in vitro or eosinophils obtained from bronchoalveolar lavage (BAL) performed after segmental lung allergen challenge of allergic subjects) demonstrated reduced binding under rotating conditions. Several L-selectin Abs inhibited adhesion of eosinophils and neutrophils (e.g., LAM1-3: 43 +/- 14% vs 63 +/- 3% inhibition; LAM1-6: 73 +/- 5% vs 36 +/- 6% inhibition, respectively, n > or = 6). Interestingly, one additional L-selectin Ab, LAM1-11, inhibited eosinophil but not neutrophil adhesion (51 +/- 2% vs 1 +/- 7% inhibition, respectively, n > or = 5). We conclude that eosinophils, like neutrophils, use L-selectin to bind to activated endothelial cells under conditions of flow, although mAb LAM1-11 can selectively inhibit eosinophil attachment to stimulated endothelial cells in vitro, suggesting different functional epitopes on L-selectin among eosinophils and neutrophils.

Authors
Knol, EF; Tackey, F; Tedder, TF; Klunk, DA; Bickel, CA; Sterbinsky, SA; Bochner, BS
MLA Citation
Knol, EF, Tackey, F, Tedder, TF, Klunk, DA, Bickel, CA, Sterbinsky, SA, and Bochner, BS. "Comparison of human eosinophil and neutrophil adhesion to endothelial cells under nonstatic conditions. Role of L-selectin." J Immunol 153.5 (September 1, 1994): 2161-2167.
PMID
7519643
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
153
Issue
5
Publish Date
1994
Start Page
2161
End Page
2167

The CD19/CD21 signal transduction complex of B lymphocytes.

CD19 and CD21 are B-cell surface molecules that associate with each other and with CD81 and Leu-13 to generate a signal transduction complex that is independent of the antigen receptor. Current studies, reviewed here by Thomas Tedder, Liang-Ji Zhou and Pablo Engel, indicate an important biological role for this protein complex in the regulation of B-cell development and activation.

Authors
Tedder, TF; Zhou, LJ; Engel, P
MLA Citation
Tedder, TF, Zhou, LJ, and Engel, P. "The CD19/CD21 signal transduction complex of B lymphocytes." Immunol Today 15.9 (September 1994): 437-442. (Review)
PMID
7524521
Source
pubmed
Published In
Immunology Today
Volume
15
Issue
9
Publish Date
1994
Start Page
437
End Page
442
DOI
10.1016/0167-5699(94)90274-7

CD20: a regulator of cell-cycle progression of B lymphocytes.

CD20 is a B-cell-specific cell-surface molecule with four membrane-spanning domains, as well as cytoplasmic N- and C-terminal domains. Here, Thomas Tedder and Pablo Engel discuss the suggestion that CD20 is a regulator of transmembrane Ca2+ conductance and plays an important functional role in B-cell activation, proliferation and differentiation.

Authors
Tedder, TF; Engel, P
MLA Citation
Tedder, TF, and Engel, P. "CD20: a regulator of cell-cycle progression of B lymphocytes." Immunol Today 15.9 (September 1994): 450-454. (Review)
PMID
7524522
Source
pubmed
Published In
Immunology Today
Volume
15
Issue
9
Publish Date
1994
Start Page
450
End Page
454
DOI
10.1016/0167-5699(94)90276-3

Role of selectins in development of adult respiratory distress syndrome.

The acute lung injury of adult respiratory distress syndrome (ARDS) is characterised by inflammatory cell accumulation and activation in the lung. Selectins are a family of adhesion molecules implicated in leucocyte-endothelial adhesion, whose receptors can exist in a cleaved, soluble form. We investigated whether circulating soluble selectin adhesion molecules, obtained from ARDS at-risk patients, were associated with subsequent ARDS development. 82 patients, at risk of ARDS, were enrolled from three well-defined groups (multiple trauma, pancreatitis, perforated bowel). Plasma samples were obtained on hospital presentation and soluble L, E, and P, selectins were quantified with a sandwich enzyme-linked immunosorbent assay (ELISA). 14 patients subsequently developed ARDS. Initial plasma soluble L-selectin (sL-selectin) levels were significantly lower in patients who progressed to ARDS compared to those who did not (p = 0.0001; 95% Cl for mean in ARDS patients as percent of that in non-ARDS patients, 27-61%). Moreover concentrations were lower than in 62 normal volunteers (range 0.37-6.55, median 1.83 micrograms/mL, n = 62), suggesting that a selective reduction of sL-selectin correlates with susceptibility. In addition, a significant correlation was found between low values of sL-selectin and indices of subsequent lung injury including requirement for ventilation (p = 0.0001) and degree of respiratory failure (p = 0.0001). A significant correlation was also found between low values of sL-selectin and patient mortality (p = 0.002). These results elucidate the inflammatory cell endothelial interactions in the early stages of ARDS and may be of prognostic value.

Authors
Donnelly, SC; Haslett, C; Dransfield, I; Robertson, CE; Carter, DC; Ross, JA; Grant, IS; Tedder, TF
MLA Citation
Donnelly, SC, Haslett, C, Dransfield, I, Robertson, CE, Carter, DC, Ross, JA, Grant, IS, and Tedder, TF. "Role of selectins in development of adult respiratory distress syndrome." Lancet 344.8917 (July 23, 1994): 215-219.
PMID
7518025
Source
pubmed
Published In
The Lancet
Volume
344
Issue
8917
Publish Date
1994
Start Page
215
End Page
219

Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice.

L-selectin, a cell adhesion molecule expressed by leukocytes, mediates the attachment of lymphocytes to high endothelial venules (HEV) of peripheral lymph nodes and mediates the earliest interactions between leukocytes and activated vascular endothelium. Mice possessing a mutant L-selectin gene that results in the complete loss of cell surface receptor expression were generated by gene targeting. Lymphocytes from these mice did not bind to peripheral lymph node HEV and these mice had a severe reduction in the number of lymphocytes localized to peripheral lymph nodes. Short-term homing experiments demonstrated that L-selectin was also involved in lymphocyte migration to mucosal lymph nodes, Peyer's patches, and spleen. Furthermore, significant defects in leukocyte rolling and neutrophil migration into the peritoneum in response to an inflammatory stimulus were observed. Thus, L-selectin plays an essential role in leukocyte homing to lymphoid tissues and sites of inflammation.

Authors
Arbonés, ML; Ord, DC; Ley, K; Ratech, H; Maynard-Curry, C; Otten, G; Capon, DJ; Tedder, TF
MLA Citation
Arbonés, ML, Ord, DC, Ley, K, Ratech, H, Maynard-Curry, C, Otten, G, Capon, DJ, and Tedder, TF. "Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice." Immunity 1.4 (July 1994): 247-260.
PMID
7534203
Source
pubmed
Published In
Immunity
Volume
1
Issue
4
Publish Date
1994
Start Page
247
End Page
260

Ligation of MHC class I and class II molecules can lead to heterologous desensitization of signal transduction pathways that regulate homotypic adhesion in human lymphocytes.

Engagement of lymphocyte MHC class I and class II Ags activates an array of intracellular signal transduction pathways that up-regulates the activity of cell-surface adhesion receptors, resulting in homotypic cell-cell aggregation. In this study, engagement of MHC class I and class II molecules with specific mAbs was shown to also inhibit lymphocyte homotypic adhesion. Two mAbs reactive with class II Ag, homotypic adhesion blocking mAb (HAB)-2, and HAB-3, and one mAb reactive with class I Ag, HAB-4, were generated that inhibited homotypic adhesion of activated lymphocytes and B and T cell lines at concentrations as low as 0.1 microgram/ml. Binding of these mAbs resulted in heterologous desensitization of other surface signal transduction molecules as homotypic adhesion induced through class I, class II, CD19, CD20, CD39, CD40, Leu-13, and PMA was also inhibited. The spontaneous adhesion exhibited by some cell lines was also abrogated by binding of these mAbs. Abs that either induced, blocked, or had no effect on adhesion bound to distinct epitopes on class I, whereas the anti-class II mAbs recognized either distinct or overlapping epitopes. Thus, engagement of distinct epitopes on MHC molecules can result in homologous or heterologous desensitization of cell-surface signaling molecules. The induction or inhibition of homotypic adhesion through class I molecules did not require the presence of the cytoplasmic domain, as deletion of this portion of the class I molecule had no effect. In contrast, the transmembrane region was essential for signal transduction as the mAbs binding to a chimeric molecule in which the transmembrane and cytoplasmic domains of class I were exchanged with those of the HB15 molecule did not induce or inhibit homotypic adhesion. Although this report is the first demonstration that homotypic adhesion can be influenced in a negative manner through MHC molecules, these findings demonstrate a considerable level of cross-talk between MHC molecules and other cell-surface receptor systems and their signal transduction pathways, and suggests that MHC class I and class II molecules may serve important roles in the regulation of adhesive events during lymphocyte activation.

Authors
Wagner, N; Engel, P; Vega, M; Tedder, TF
MLA Citation
Wagner, N, Engel, P, Vega, M, and Tedder, TF. "Ligation of MHC class I and class II molecules can lead to heterologous desensitization of signal transduction pathways that regulate homotypic adhesion in human lymphocytes." J Immunol 152.11 (June 1, 1994): 5275-5287.
PMID
7514635
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
152
Issue
11
Publish Date
1994
Start Page
5275
End Page
5287

Monocyte rolling, arrest and spreading on IL-4-activated vascular endothelium under flow is mediated via sequential action of L-selectin, beta 1-integrins, and beta 2-integrins.

Leukocyte interactions with vascular endothelium at sites of inflammation can be dynamically regulated by activation-dependent adhesion molecules. Current models, primarily based on studies with polymorphonuclear leukocytes, suggest the involvement of multiple members of the selectin, integrin, and immunoglobulin gene families, sequentially, in the process of initial attachment (rolling), stable adhesion (arrest), spreading and ultimate diapedesis. In the current study, IL-4-activated human umbilical vein endothelium, which selectively expresses VCAM-1 and an L-selectin ligand but not E-selectin, and appropriate function blocking monoclonal antibodies, were used to study monocyte-endothelial interactions in an in vitro model that mimics microcirculatory flow conditions. In this system, L-selectin mediates monocyte rolling and also facilitates alpha 4 beta 1-integrin-dependent arrest, whereas beta 2-integrins are required for spreading of firmly attached monocytes on the endothelial cell surface but not their arrest. These findings provide the first in vitro evidence for human monocyte rolling on cytokine-activated endothelium, and suggest a sequential requirement for both beta 1- and beta 2-integrin-dependent adhesive mechanisms in monocyte-endothelial interactions.

Authors
Luscinskas, FW; Kansas, GS; Ding, H; Pizcueta, P; Schleiffenbaum, BE; Tedder, TF; Gimbrone, MA
MLA Citation
Luscinskas, FW, Kansas, GS, Ding, H, Pizcueta, P, Schleiffenbaum, BE, Tedder, TF, and Gimbrone, MA. "Monocyte rolling, arrest and spreading on IL-4-activated vascular endothelium under flow is mediated via sequential action of L-selectin, beta 1-integrins, and beta 2-integrins." J Cell Biol 125.6 (June 1994): 1417-1427.
PMID
7515891
Source
pubmed
Published In
The Journal of Cell Biology
Volume
125
Issue
6
Publish Date
1994
Start Page
1417
End Page
1427

Tissue-specific expression of the human CD19 gene in transgenic mice inhibits antigen-independent B-lymphocyte development.

CD19 is a B-cell-specific member of the immunoglobulin superfamily expressed from early pre-B-cell development until plasma cell differentiation. In vitro studies demonstrate that the CD19 signal transduction molecule can serve as a costimulatory molecule for activation through other B-lymphocyte cell surface molecules. However, much remains to be known regarding how CD19 functions in vivo and whether CD19 has different roles at particular stages of B-cell differentiation. Therefore, transgenic mice overexpressing the human CD19 (hCD19) gene were generated to determine whether this transgene would be expressed in a B-lineage-specific fashion and to dissect the in vivo role of CD19 in B-cell development and activation. Expression of the human transgene product was specifically restricted to all B-lineage cells and appeared early in development as occurs with hCD19. In addition, expression of hCD19 severely impaired the development of immature B cells in the bone marrow, with dramatically fewer B cells found in the spleen, peripheral circulation, and peritoneal cavity. The level of hCD19 expressed on the cell surface correlated directly with the severity of the defect in different transgenic lines. These results demonstrate that the hCD19 gene is expressed in a lineage-specific fashion in mice, indicating that the hCD19 gene may be useful for mediating B-lineage-specific expression of other transgene products. In addition, these results indicate an important role for the lineage-specific CD19 molecule during early B-cell development before antigen-dependent activation.

Authors
Zhou, LJ; Smith, HM; Waldschmidt, TJ; Schwarting, R; Daley, J; Tedder, TF
MLA Citation
Zhou, LJ, Smith, HM, Waldschmidt, TJ, Schwarting, R, Daley, J, and Tedder, TF. "Tissue-specific expression of the human CD19 gene in transgenic mice inhibits antigen-independent B-lymphocyte development." Mol Cell Biol 14.6 (June 1994): 3884-3894.
PMID
7515149
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
14
Issue
6
Publish Date
1994
Start Page
3884
End Page
3894

Residues within a conserved amino acid motif of domains 1 and 4 of VCAM-1 are required for binding to VLA-4.

Vascular cell adhesion molecule 1 (VCAM-1), a member of the Ig superfamily originally identified on activated endothelium, binds to the integrin very late antigen-4 (VLA-4), also known as alpha 4 beta 1 or CD49d/CD29, to support cell-cell adhesion. Studies based on cell adhesion to two alternatively spliced forms of VCAM-1 or to chimeric molecules generated from them and intercellular adhesion molecule-1 (ICAM-1) have demonstrated two VLA-4 binding sites on the predominate form of VCAM-1. Here, we studied VLA-4-dependent adhesion of the lymphoid tumor cell line Ramos to cells expressing wild type and mutant forms of VCAM-1. Results based on domain deletion mutants demonstrated the existence and independence of two VLA-4-binding sites located in the first and fourth domains of VCAM-1. Results based on amino acid substitution mutants demonstrated that residues within a linear sequence of six amino acids found in both domain 1 and 4 were required for VLA-4 binding to either domain. Five of these amino acids represent a conserved motif also found in ICAM domains. We propose that integrin binding to these Ig-like domains depends on residues within this conserved motif. Specificity of integrin binding to Ig-like domains may be regulated by a set of nonconserved residues distinct from the conserved motif.

Authors
Vonderheide, RH; Tedder, TF; Springer, TA; Staunton, DE
MLA Citation
Vonderheide, RH, Tedder, TF, Springer, TA, and Staunton, DE. "Residues within a conserved amino acid motif of domains 1 and 4 of VCAM-1 are required for binding to VLA-4." J Cell Biol 125.1 (April 1994): 215-222.
PMID
7511143
Source
pubmed
Published In
The Journal of Cell Biology
Volume
125
Issue
1
Publish Date
1994
Start Page
215
End Page
222

HUMAN CD4+ T-LYMPHOCYTES ROLL AND ARREST ON TNF-ALPHA-ACTIVATED ENDOTHELIUM UNDER DEFINED FLOW

Authors
LUSCINSKAS, FW; DING, H; TEDDER, TF; LICHTMAN, AH
MLA Citation
LUSCINSKAS, FW, DING, H, TEDDER, TF, and LICHTMAN, AH. "HUMAN CD4+ T-LYMPHOCYTES ROLL AND ARREST ON TNF-ALPHA-ACTIVATED ENDOTHELIUM UNDER DEFINED FLOW." FASEB JOURNAL 8.4 (March 1994): A322-A322.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
8
Issue
4
Publish Date
1994
Start Page
A322
End Page
A322

A role for the epidermal growth factor-like domain of P-selectin in ligand recognition and cell adhesion.

The selectin family of adhesion molecules mediates the initial interactions of leukocytes with endothelium. The extracellular region of each selectin contains an amino-terminal C-type lectin domain, followed by an EGF-like domain and multiple short consensus repeat units (SCR). Previous studies have indirectly suggested a role for each of the extracellular domains of the selectins in cell adhesion. In this study, a panel of chimeric selectins created by exchange of domains between L- and P-selectin was used to directly examine the role of the extracellular domains in cell adhesion. Exchange of only the lectin domains between L- and P-selectin conferred the adhesive and ligand recognition functions of the lectin domain of the parent molecule. However, chimeric selectins which contained both the lectin domain of L-selectin and the EGF-like domain of P-selectin exhibited dual ligand-binding specificity. These chimeric proteins supported adhesion both to myeloid cells and to high endothelial venules (HEV) of lymph nodes and mesenteric venules in vivo. Exchange of the SCR domains had no detectable effect on receptor function or specificity. Thus, the EGF-like domain of P-selectin may play a direct role in ligand recognition and leukocyte adhesion mediated by P-selectin, with the lectin plus EGF-like domains collectively forming a functional ligand recognition unit.

Authors
Kansas, GS; Saunders, KB; Ley, K; Zakrzewicz, A; Gibson, RM; Furie, BC; Furie, B; Tedder, TF
MLA Citation
Kansas, GS, Saunders, KB, Ley, K, Zakrzewicz, A, Gibson, RM, Furie, BC, Furie, B, and Tedder, TF. "A role for the epidermal growth factor-like domain of P-selectin in ligand recognition and cell adhesion." J Cell Biol 124.4 (February 1994): 609-618.
PMID
7508943
Source
pubmed
Published In
The Journal of Cell Biology
Volume
124
Issue
4
Publish Date
1994
Start Page
609
End Page
618

MOLECULAR-BASIS FOR L-SELECTIN FUNCTION IN COMPARISON WITH P-SELECTIN AND E-SELECTIN

Authors
TEDDER, TF; SAUNDERS, KB; KANSAS, GS; LEY, K; ZAKRZEWICZ, A; GIBSON, RM; FURIE, BC; FURIE, B
MLA Citation
TEDDER, TF, SAUNDERS, KB, KANSAS, GS, LEY, K, ZAKRZEWICZ, A, GIBSON, RM, FURIE, BC, and FURIE, B. "MOLECULAR-BASIS FOR L-SELECTIN FUNCTION IN COMPARISON WITH P-SELECTIN AND E-SELECTIN." JOURNAL OF CELLULAR BIOCHEMISTRY (January 4, 1994): 311-311.
Source
wos-lite
Published In
Journal of Cellular Biochemistry
Publish Date
1994
Start Page
311
End Page
311

MOLECULAR-BASIS FOR L-SELECTIN FUNCTION IN COMPARISON WITH P-SELECTIN AND E-SELECTIN

Authors
TEDDER, TF; SAUNDERS, KB; KANSAS, GS; LEY, K; ZAKRZEWICZ, A; GIBSON, RM; FURIE, BC; FURIE, B
MLA Citation
TEDDER, TF, SAUNDERS, KB, KANSAS, GS, LEY, K, ZAKRZEWICZ, A, GIBSON, RM, FURIE, BC, and FURIE, B. "MOLECULAR-BASIS FOR L-SELECTIN FUNCTION IN COMPARISON WITH P-SELECTIN AND E-SELECTIN." JOURNAL OF CELLULAR BIOCHEMISTRY (January 4, 1994): 261-261.
Source
wos-lite
Published In
Journal of Cellular Biochemistry
Publish Date
1994
Start Page
261
End Page
261

CD Antigens 1993

Authors
Schlossman, SF; Boumsell, L; Gilks, W; Harlan, JM; Kishimoto, T; Morimoto, C; Ritz, J; Shaw, S; Silverstein, RL; Springer, TA; Tedder, TF; Todd, RF
MLA Citation
Schlossman, SF, Boumsell, L, Gilks, W, Harlan, JM, Kishimoto, T, Morimoto, C, Ritz, J, Shaw, S, Silverstein, RL, Springer, TA, Tedder, TF, and Todd, RF. "CD Antigens 1993." Leukemia & Lymphoma 13.sup1 (January 1994): 59-60.
Source
crossref
Published In
Leukemia & Lymphoma (Informa)
Volume
13
Issue
sup1
Publish Date
1994
Start Page
59
End Page
60
DOI
10.3109/10428199409052676

New CD from the B cell section of the Fifth International Workshop on Human Leukocyte Differentiation Antigens.

This review summaries the expression and the molecular and biochemical characteristics of eight new Clusters of Differentiation (CD79-CD86) established by the B cell Section during the Fifth International Workshop on Human Leukocyte Differentiation Antigens. CD79 monoclonal antibodies (mAb) identify the mbl (CD79 alpha) and B29 (CD79 beta) components of the surface immunoglobulin (Ig) receptor complex. CD80 (B7/BB-1) is a costimulatory molecule that serves as the ligand for two molecules expressed on T lymphocytes, CD28 and CTLA-4. CD81 (TAPA-1) and CD82 (R2) are new members of the tetra-spans family of transmembrane proteins, which include CD9, CD37, CD53 and CD63. These proteins are postulated to be involved in signal transduction. CD83 (HB15) is a marker for human interdigitating reticulum cells, circulating dendritic cells and Langerhans cells. CDw84 and CD85 are new B cell-associated molecules that are also expressed by monocytes. CD86 is a new B cell activation antigen.

Authors
Engel, P; Tedder, TF
MLA Citation
Engel, P, and Tedder, TF. "New CD from the B cell section of the Fifth International Workshop on Human Leukocyte Differentiation Antigens." Leuk Lymphoma 13 Suppl 1 (1994): 61-64. (Review)
PMID
8075582
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
13 Suppl 1
Publish Date
1994
Start Page
61
End Page
64
DOI
10.3109/10428199409052677

CD19 maps to a region of conservation between human chromosome 16 and mouse chromosome 7.

CD19 is a B lymphocyte cell surface protein expressed from the earliest stages of B lymphocyte development until their terminal differentiation into plasma cells. In this report the human CD19 gene (hCD19) was localized to band p11.2 on the proximal short arm of chromosome 16 by in situ hybridization to metaphase chromosomes, using hCD19 cDNA as probe. hCD19 gene localization was confirmed by polymerase chain reaction based analysis with hCD19-specific primers, using a panel of human/hamster somatic cell hybrid DNA as templates. The mouse CD19 gene (mCd19) was mapped to bands F3-F4 of chromosome 7 by in situ hybridization to metaphase chromosomes, using a mCD19 cDNA probe. Segregation analysis of nucleotide sequence polymorphisms in interspecific backcross progeny revealed linkage of mCd19 with hemoglobin beta (Hbb), Int-2, and H19, other loci previously mapped to the same region of mouse chromosome 7, confirming the localization of mCd19 to this region. The order of these loci was determined to be centromere--Hbb--mCd19--H19--Int-2--telomere. The genetic distances between the loci examined, calculated from the recombination frequencies, suggested that mCd19 was located centrally between Hbb and H19. This region of mouse chromosome 7 is homologous to the region of human chromosome 16 to which the hCD19 gene maps. Multiple genes with a lymphocyte-related function also map to this conserved region including genes encoding the IL-4 receptor, CD11a, CD11b, CD11c, CD43 (leukosialin), and protein kinase C beta polypeptide.

Authors
Ord, DC; Edelhoff, S; Dushkin, H; Zhou, LJ; Beier, DR; Disteche, C; Tedder, TF
MLA Citation
Ord, DC, Edelhoff, S, Dushkin, H, Zhou, LJ, Beier, DR, Disteche, C, and Tedder, TF. "CD19 maps to a region of conservation between human chromosome 16 and mouse chromosome 7." Immunogenetics 39.5 (1994): 322-328.
PMID
7513297
Source
pubmed
Published In
Immunogenetics
Volume
39
Issue
5
Publish Date
1994
Start Page
322
End Page
328

CD antigens 1993

Authors
Schlossman, SF; Boumsell, L; Gilks, W; Harlan, JM; Kishimoto, T; Morimoto, C; Ritz, J; Shaw, S; Silverstein, RL; Springer, TA; Tedder, TF; Todd, RF
MLA Citation
Schlossman, SF, Boumsell, L, Gilks, W, Harlan, JM, Kishimoto, T, Morimoto, C, Ritz, J, Shaw, S, Silverstein, RL, Springer, TA, Tedder, TF, and Todd, RF. "CD antigens 1993." Trends in Immunology 15.3 (1994): 98-99.
PMID
7909665
Source
scival
Published In
Trends in Immunology
Volume
15
Issue
3
Publish Date
1994
Start Page
98
End Page
99

CD antigens 1993

Authors
Schlossman, SF; Boumsell, L; Gilks, W; Harlan, JM; Kishimoto, T; Morimoto, C; Ritz, J; Shaw, S; Silverstein, RL; Springer, TA; Tedder, TF; Todd, RF
MLA Citation
Schlossman, SF, Boumsell, L, Gilks, W, Harlan, JM, Kishimoto, T, Morimoto, C, Ritz, J, Shaw, S, Silverstein, RL, Springer, TA, Tedder, TF, and Todd, RF. "CD antigens 1993." Immunology Today 15.3 (1994): 98--.
Source
scival
Published In
Immunology Today
Volume
15
Issue
3
Publish Date
1994
Start Page
98-

CD antigens 1993

Authors
Schlossman, SF; Boumsell, L; Gilks, W; Harlan, JM; Kishimoto, T; Morimoto, C; Ritz, J; Shaw, S; Silverstein, RL; Springer, TA; Tedder, TF; Todd, RF
MLA Citation
Schlossman, SF, Boumsell, L, Gilks, W, Harlan, JM, Kishimoto, T, Morimoto, C, Ritz, J, Shaw, S, Silverstein, RL, Springer, TA, Tedder, TF, and Todd, RF. "CD antigens 1993." Leukemia and Lymphoma 13.SUPPL. 1 (1994): 59-60.
Source
scival
Published In
Leukemia and Lymphoma
Volume
13
Issue
SUPPL. 1
Publish Date
1994
Start Page
59
End Page
60

CD antigens 1993

Authors
Schlossman, SF; Boumsell, L; Gilks, W; Harlan, JM; Kishimoto, T; Morimoto, C; Ritz, J; Shaw, S; Silverstein, RL; Springer, TA; Tedder, TF; Todd, RF
MLA Citation
Schlossman, SF, Boumsell, L, Gilks, W, Harlan, JM, Kishimoto, T, Morimoto, C, Ritz, J, Shaw, S, Silverstein, RL, Springer, TA, Tedder, TF, and Todd, RF. "CD antigens 1993." Journal of Immunology 152.1 (1994): 1-2.
PMID
7902854
Source
scival
Published In
Journal of Immunology
Volume
152
Issue
1
Publish Date
1994
Start Page
1
End Page
2

CD antigens 1993: An updated nomenclature for clusters of differentiation on human cells

The 5th International Workshop on Human Leukocyte Differentiation Antigens (Boston, USA, 3-7 November 1993) recommended the adoption of 48 new CD clusters and subclusters and the redefinition of 14 previously established clusters. The additions and changes made to the existing CD nomenclature are summarized in a Table.

Authors
Schlossmann, SF; Boumsell, L; Gilks, W; Harlan, JM; Kishimoto, T; Morimoto, C; Ritz, J; Shaw, S; Silverstein, RL; Springer, TA; Tedder, TF; Todd, RF
MLA Citation
Schlossmann, SF, Boumsell, L, Gilks, W, Harlan, JM, Kishimoto, T, Morimoto, C, Ritz, J, Shaw, S, Silverstein, RL, Springer, TA, Tedder, TF, and Todd, RF. "CD antigens 1993: An updated nomenclature for clusters of differentiation on human cells." Bulletin of the World Health Organization 72.5 (1994): 807-808.
PMID
7955032
Source
scival
Published In
Bulletin of the World Health Organization
Volume
72
Issue
5
Publish Date
1994
Start Page
807
End Page
808

CD20: A regulator of cell-cycle progression of B lymphocytes

CD20 is a B-cell-specific cell-surface molecule with four membrane-spanning domains, as well as cytoplasmic N- and C-terminal domains. Here, Thomas Tedder and Pablo Engel discuss the suggestion that CD20 is a regulator of transmembrane Ca2+ conductance and plays an important functional role in B-cell activation, proliferation and differentiation.

Authors
Tedder, TF; Engel, P
MLA Citation
Tedder, TF, and Engel, P. "CD20: A regulator of cell-cycle progression of B lymphocytes." Immunology Today 15.9 (1994): 450-454.
Source
scival
Published In
Immunology Today
Volume
15
Issue
9
Publish Date
1994
Start Page
450
End Page
454
DOI
10.1016/0167-5699(94)90276-3

CD antigens 1993

Authors
Schlossman, SF; Boumsell, L; Gilks, W; Harlan, JM; Kishimoto, T; Morimoto, C; Ritz, J; Shaw, S; Silverstein, RL; Springer, TA; Tedder, TF; Todd, RF
MLA Citation
Schlossman, SF, Boumsell, L, Gilks, W, Harlan, JM, Kishimoto, T, Morimoto, C, Ritz, J, Shaw, S, Silverstein, RL, Springer, TA, Tedder, TF, and Todd, RF. "CD antigens 1993." Blood 83.4 (1994): 879-880.
PMID
8111060
Source
scival
Published In
Blood
Volume
83
Issue
4
Publish Date
1994
Start Page
879
End Page
880

The CD19/CD21 signal transduction complex of B lymphocytes

CD19 and CD21 are B-cell surface molecules that associate with each other and with CD81 and Leu-13 to generate a signal transduction complex that is independent of the antigen receptor. Current studies, reviewed here by Thomas Tedder, Liang-Ji Zhou and Pablo Engel, indicate an important biological role for this protein complex in the regulation of B-cell development and activation.

Authors
Tedder, TF; Zhou, L-J; Engel, P
MLA Citation
Tedder, TF, Zhou, L-J, and Engel, P. "The CD19/CD21 signal transduction complex of B lymphocytes." Immunology Today 15.9 (1994): 437-442.
Source
scival
Published In
Immunology Today
Volume
15
Issue
9
Publish Date
1994
Start Page
437
End Page
442
DOI
10.1016/0167-5699(94)90274-7

The CD19 signal transduction complex of B lymphocytes. Deletion of the CD19 cytoplasmic domain alters signal transduction but not complex formation with TAPA-1 and Leu 13.

CD19 expressed on the surface of B lymphocytes is a key member of a cell surface signal transduction complex that includes TAPA-1, Leu 13 and CD21. The human CD19 protein is composed of 540 amino acids with a cytoplasmic domain of 242 amino acids. Although the cytoplasmic domain of CD19 has no sequence homology with other proteins, the cytoplasmic domain of human, mouse, and guinea pig CD19 is highly conserved suggesting that this region of CD19 is at least partially responsible for signaling activity. In this study, the regions of CD19 required for intermolecular associations and signal transduction were determined by comparing a series of carboxyl-terminal cytoplasmic tail deletion mutants and a CD19/L-selectin chimera with native CD19. CD19 expressed in the human Rex T cell line and the K562 erythroleukemia cell line generated transmembrane signals and also associated with endogenous TAPA-1. Deletion of 95% of the CD19 cytoplasmic domain did not affect the ability of CD19 to be expressed or to associate with TAPA-1. However, replacement of the CD19 transmembrane and cytoplasmic domains with those of L-selectin (CD19-LAM) resulted in the loss of CD19 complex formation, suggesting that the membrane spanning domain is critical for this association. Similarly, the induction of homotypic adhesion through CD19 or truncated CD19 was equivalent, whereas homotypic adhesion was not induced via the CD19-LAM chimera. In addition, the cytoplasmic domain was not necessary for CD19 mAb-mediated growth inhibition or internalization. In contrast, the CD19 cytoplasmic domain was required for optimal mAb-induced increases in [Ca2+]i in CD19 cDNA-transfected Rex cells. Thus, the CD19 cytoplasmic domain is responsible for the induction of increased [Ca2+]i, and the transmembrane region is required for cell surface associations with the other members of the CD19 complex and most signaling events. Therefore, mAb binding to CD19 is likely to initiate multiple intracellular signal transduction cascades either through CD19 directly, or through other members of the CD19 complex.

Authors
Bradbury, LE; Goldmacher, VS; Tedder, TF
MLA Citation
Bradbury, LE, Goldmacher, VS, and Tedder, TF. "The CD19 signal transduction complex of B lymphocytes. Deletion of the CD19 cytoplasmic domain alters signal transduction but not complex formation with TAPA-1 and Leu 13." J Immunol 151.6 (September 15, 1993): 2915-2927.
PMID
7690791
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
151
Issue
6
Publish Date
1993
Start Page
2915
End Page
2927

L-selectin can mediate leukocyte rolling in untreated mesenteric venules in vivo independent of E- or P-selectin.

Granulocyte recruitment during the acute inflammatory response is initiated by their rolling along the endothelial lining of postcapillary venules. To determine whether expression of L-selectin alone is sufficient for rolling, the murine pre-B lymphocytic cell line 300.19, which does not bind E- or P-selectin, was transfected with human L-selectin cDNA, which led to stable L-selectin expression at a level similar to that of blood lymphocytes. Fluorescent-labeled cells were infused retrogradely into a side branch of the superior mesenteric artery of anesthetized rats. In venules of the mesenteric membrane, leukocyte rolling occurs without intentional stimulation. On average, 17% +/- 6% of L-selectin transfectants rolled in the observed venules, while mock-transfected cells did not roll. Rolling of L-selectin transfectants began approximately 20 minutes after surgery and continued for at least 120 minutes. In contrast, HL-60 promyelocytes, which express sialyl-Lewis(x) tetrasaccharide (sLe(x)) but not L-selectin and that bind to E- and P-selectin in vitro, did not roll between 20 and 120 minutes, but some HL-60 cells rolled at very early (< 20 minutes) and late (> 2 hours) time points. Pretreatment with either of two function-blocking monoclonal antibodies recognizing the lectin domain of L-selectin completely blocked rolling of L-selectin transfectants and sharply reduced (by 70%) rolling of isolated human granulocytes. Taken together, these results show that L-selectin can mediate leukocyte rolling by virtue of its lectin activity.

Authors
Ley, K; Tedder, TF; Kansas, GS
MLA Citation
Ley, K, Tedder, TF, and Kansas, GS. "L-selectin can mediate leukocyte rolling in untreated mesenteric venules in vivo independent of E- or P-selectin." Blood 82.5 (September 1, 1993): 1632-1638.
PMID
7689875
Source
pubmed
Published In
Blood
Volume
82
Issue
5
Publish Date
1993
Start Page
1632
End Page
1638

Regulation of leukocyte migration by L-selectin: mechanisms, domains and ligands.

Authors
Tedder, TF; Luscinskas, W; Kansas, GS
MLA Citation
Tedder, TF, Luscinskas, W, and Kansas, GS. "Regulation of leukocyte migration by L-selectin: mechanisms, domains and ligands." Behring Inst Mitt 92 (August 1993): 165-177. (Review)
PMID
7504448
Source
pubmed
Published In
Behring Institute Mitteilungen
Issue
92
Publish Date
1993
Start Page
165
End Page
177

Regulation of the tyrosine kinase-dependent adhesion pathway in human lymphocytes through CD45.

Cell-cell adhesive interactions involve numerous receptor/ligand interactions that play a crucial role in the development of immune function. Engagement of multiple cell-surface molecules on B lymphocytes generates intracellular signals through a tyrosine kinase-dependent pathway that activates cell-surface adhesion receptors and thereby induces homotypic cell-cell adhesion. Homotypic adhesion is mediated in part through LFA-1/ICAM-1 and other heretofore unknown adhesion receptors. In this study, evidence of a regulatory role for CD45 in the induction of homotypic adhesion is suggested. A new mAb (HAB-1) was developed that inhibits homotypic adhesion in B cell lines induced through MHC class I and class II, CD19, CD20, CD21, CD40, and Leu-13 cell-surface molecules. Although binding of this mAb strongly inhibited cell-surface Ag-induced homotypic adhesion at mAb concentrations as low as 0.1 microgram/ml, it exhibited no effect on homotypic adhesion induced by phorbol esters. Binding of the HAB-1 mAb to lymphocytes altered the pattern of cellular protein tyrosine phosphorylation, but did not have a global inhibitory effect on cell activation because it did not have major effects on the growth of mitogen-activated lymphocytes. Immunoprecipitation studies revealed that the HAB-1 mAb identified an epitope present on all isoforms of CD45. The HAB-1 mAb may identify a unique epitope of CD45 because this mAb had a unique staining pattern when assessed by indirect immunofluorescence staining. The HAB-1 mAb was similar to some other CD45 mAb that have the capacity to amplify CD2-induced proliferation of blood lymphocytes. However, only 1 of 12 other anti-CD45 mAb tested had a similar inhibitory effect on adhesion. Homotypic adhesion of lymphocytes may therefore be governed by a regulatory system of cell-surface molecules that generate positive and negative signals that either trigger adhesion or, like CD45, directly down-regulate adhesion. This highlights the significance of adhesive events that result from surface molecules being engaged by their natural ligands during lymphocyte activation.

Authors
Wagner, N; Engel, P; Tedder, TF
MLA Citation
Wagner, N, Engel, P, and Tedder, TF. "Regulation of the tyrosine kinase-dependent adhesion pathway in human lymphocytes through CD45." J Immunol 150.11 (June 1, 1993): 4887-4899.
PMID
7684415
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
150
Issue
11
Publish Date
1993
Start Page
4887
End Page
4899

The same epitope on CD22 of B lymphocytes mediates the adhesion of erythrocytes, T and B lymphocytes, neutrophils, and monocytes.

CD22 is a B lineage-restricted member of the Ig superfamily that serves as an adhesion receptor expressed by mature B lymphocytes. In this study, the ability of different cell types to attach to COS cells transiently transfected with a full-length CD22 cDNA (COS-CD22) was examined to determine the cellular distribution of the ligand for CD22. T and B lymphocytes, monocytes, erythrocytes, and neutrophils formed specific rosettes with COS-CD22 cells at 4 degrees C. A panel of 33 new mAb directed against CD22 were developed to examine the regions of CD22 that mediate adhesion. Four of these mAb, HB22-7, -22, -23, and -33 (at 1 to 5 micrograms/ml) specifically blocked adhesion (75 to 95%) of all cell types to COS-CD22 cells. Each of these mAb cross-blocked each other's binding, suggesting that ligand binding occurs through a single region of CD22. These mAb also identify a region of CD22 distinct from those defined by previously described CD22 mAb. CD22-mediated adhesion of cell lines to COS-CD22 cells was independent of CD45RO and CDw75 expression, and it was not inhibited by mAb against known integrins. Although alpha-2,6-linked sialic acid expressed on the surface of COS cells did not serve as a ligand for CD22, the CD22 ligand may contain a critical sialic acid determinant, as neuraminidase treatment of all target cells eliminated CD22-mediated adhesion. CD22-mediated adhesion was Ca2+/Mg2+ independent, again suggesting that integrins were not involved. An inhibitory substance for CD22-mediated adhesion was found to be present in FCS and some ascites fluid. Analysis of CD22 mRNA and protein revealed that although multiple mRNA splice variants of CD22 mRNA can be detected, only a single protein isoform was detected on the cell surface. Therefore, although the identity of the CD22 ligands remains incompletely characterized, it is possible that a single major ligand is expressed by RBC and leukocytes, which binds to a single region of CD22.

Authors
Engel, P; Nojima, Y; Rothstein, D; Zhou, LJ; Wilson, GL; Kehrl, JH; Tedder, TF
MLA Citation
Engel, P, Nojima, Y, Rothstein, D, Zhou, LJ, Wilson, GL, Kehrl, JH, and Tedder, TF. "The same epitope on CD22 of B lymphocytes mediates the adhesion of erythrocytes, T and B lymphocytes, neutrophils, and monocytes." J Immunol 150.11 (June 1, 1993): 4719-4732.
PMID
7684411
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
150
Issue
11
Publish Date
1993
Start Page
4719
End Page
4732

Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes.

CD20 is a plasma membrane phosphoprotein expressed exclusively by B lymphocytes. mAb binding to CD20 alters cell cycle progression and differentiation, indicating that CD20 plays an essential role in B lymphocyte function. Whole-cell patch clamp and fluorescence microscopy measurements of plasma membrane ionic conductance and cytosolic-free Ca2+ activity, respectively, were used to directly examine CD20 function. Transfection of human T and mouse pre-B lymphoblastoid cell lines with CD20 cDNA and subsequent stable expression of CD20 specifically increased transmembrane Ca2+ conductance. Transfection of CD20 cDNA and subsequent expression of CD20 in nonlymphoid cells (human K562 erythroleukemia cells and mouse NIH-3T3 fibroblasts) also induced the expression of an identical transmembrane Ca2+ conductance. The binding of a CD20-specific mAb to CD20+ lymphoblastoid cells also enhanced the transmembrane Ca2+ conductance. The mAb-enhanced Ca2+ currents had the same conductance characteristics as the CD20-associated Ca2+ currents in CD20 cDNA-transfected cells. C20 is structurally similar to several ion channels; each CD20 monomer possesses four membrane spanning domains, and both the amino and carboxy termini reside within the cytoplasm. Biochemical cross-linking of cell-surface molecules with subsequent immunoprecipitation analysis of CD20 suggests that CD20 may be present as a multimeric oligomer within the membrane, as occurs with several known membrane channels. Taken together, these findings indicate that CD20 directly regulates transmembrane Ca2+ conductance in B lymphocytes, and suggest that multimeric complexes of CD20 may form Ca2+ conductive ion channels in the plasma membrane of B lymphoid cells.

Authors
Bubien, JK; Zhou, LJ; Bell, PD; Frizzell, RA; Tedder, TF
MLA Citation
Bubien, JK, Zhou, LJ, Bell, PD, Frizzell, RA, and Tedder, TF. "Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes." J Cell Biol 121.5 (June 1993): 1121-1132.
PMID
7684739
Source
pubmed
Published In
The Journal of Cell Biology
Volume
121
Issue
5
Publish Date
1993
Start Page
1121
End Page
1132

Isolation and characterization of a bovine cDNA encoding a functional homolog of human P-selectin.

A cDNA encoding a homologue of human P-selectin has been isolated from a bovine capillary endothelial cDNA library. The 2.7 kb cDNA encodes a 646 amino acid polypeptide with 77% identity to the human P-selectin except that it lacks three of the consensus repeat domains found in human P-selectin. Human P-selectin, expressed in platelets and endothelium, is a Ca(2+)-dependent receptor for myeloid cells that binds to carbohydrates on neutrophils and monocytes. To determine if bovine P-selectin exhibits a similar binding activity, its cDNA was expressed in COS cells and the ability of the transfectants to bind HL-60 human myelogenous leukemia cells was examined. The bovine P-selectin bound the myeloid cells in a manner similar to human P-selectin, indicating that the altered domain structure of bovine P-selectin does not affect P-selectin function in this in vitro cell adhesion assay.

Authors
Strubel, NA; Nguyen, M; Kansas, GS; Tedder, TF; Bischoff, J
MLA Citation
Strubel, NA, Nguyen, M, Kansas, GS, Tedder, TF, and Bischoff, J. "Isolation and characterization of a bovine cDNA encoding a functional homolog of human P-selectin." Biochem Biophys Res Commun 192.2 (April 30, 1993): 338-344.
PMID
7683458
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
192
Issue
2
Publish Date
1993
Start Page
338
End Page
344
DOI
10.1006/bbrc.1993.1420

Regulation of leukocyte rolling and adhesion to high endothelial venules through the cytoplasmic domain of L-selectin.

L-selectin (leukocyte adhesion molecule 1/MEL-14), a member of the selectin family of cell adhesion molecules, mediates leukocyte rolling and leukocyte adhesion to endothelium at sites of inflammation. In addition, L-selectin mediates the binding of lymphocytes to high endothelial venules (HEV) of peripheral lymph nodes. The strong amino acid sequence conservation of the cytoplasmic domain of L-selectin between humans and mice suggests an important role for this region. Deletion of the COOH-terminal 11 amino acids from the approximately 17 amino acid cytoplasmic domain of L-selectin eliminated binding of lymphocytes to HEV in the in vitro frozen section assay, and also abolished leukocyte rolling in vivo in exteriorized rat mesenteric venules, but did not alter the lectin activity of L-selectin. Pretreatment of cells with cytochalasin B, which disrupts actin microfilaments, also abolished adhesion without affecting carbohydrate recognition. Therefore, the cytoplasmic domain of L-selectin regulates leukocyte adhesion to endothelium independent of ligand recognition, by controlling cytoskeletal interactions and/or receptor avidity.

Authors
Kansas, GS; Ley, K; Munro, JM; Tedder, TF
MLA Citation
Kansas, GS, Ley, K, Munro, JM, and Tedder, TF. "Regulation of leukocyte rolling and adhesion to high endothelial venules through the cytoplasmic domain of L-selectin." J Exp Med 177.3 (March 1, 1993): 833-838.
PMID
7679710
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
177
Issue
3
Publish Date
1993
Start Page
833
End Page
838

Syn-capping of human T lymphocyte adhesion/activation molecules and their redistribution during interaction with endothelial cells.

Lymphocyte-endothelial cell interactions are mediated in part by multiple lymphocyte surface adhesion/activation molecules and their cognate ligands. We investigated the surface localization of several of these molecules implicated in T cell adhesion and transendothelial migration mechanisms to determine if spatial regulation of their distribution contributes to these processes. T lymphocyte suspensions were stained to define distribution, ability to be aggregated into energy-dependent caps, and potential cocapping of several adhesion structures. CD2, CD44, L-selectin (LAM-1, LECCAM-1), and CD11a/CD18 (LFA-1) exhibited uniform distribution on the T cell surface by direct immunofluorescence but formed caps in an energy-dependent, and therefore cytoskeletally driven, manner when examined by indirect immunofluorescence. CD2 was shown to syn-cap (unidirectionally cocap) with CD44 and CD11a/CD18 (LFA-1), an observation potentially related to functional cooperation among these molecules in T cell activation. T cells were also added to endothelial cell monolayers to assess, in a physiologically relevant context, potential surface molecule reorganization. Lymphocytes co-cultured with human umbilical vein endothelial cells (HUVEC) underwent a profound shape change, from essentially round cells to polarized cells bearing pseudopodia. Immunofluorescent localization of T cell adhesion/activation molecules using confocal microscopy revealed the redistribution of CD2, CD44, and L-selectin to the pseudopod. In contrast, CD11a/CD18 remained globally distributed on the cell surface, even in severely deformed cells. Both lymphocyte shape change and membrane molecule redistribution appear to be cell-cell contact-dependent phenomena requiring intact, viable endothelial cells. Mechanisms that control these events may be critical to lymphocyte recirculation and inflammation.

Authors
Rosenman, SJ; Ganji, AA; Tedder, TF; Gallatin, WM
MLA Citation
Rosenman, SJ, Ganji, AA, Tedder, TF, and Gallatin, WM. "Syn-capping of human T lymphocyte adhesion/activation molecules and their redistribution during interaction with endothelial cells." J Leukoc Biol 53.1 (January 1993): 1-10.
PMID
7678845
Source
pubmed
Published In
Journal of leukocyte biology
Volume
53
Issue
1
Publish Date
1993
Start Page
1
End Page
10

REGULATION OF LEUKOCYTE-ENDOTHELIUM INTERACTIONS THROUGH L-SELECTIN

Authors
TEDDER, TF; LUSCINSKAS, FW; SAUNDERS, KB
MLA Citation
TEDDER, TF, LUSCINSKAS, FW, and SAUNDERS, KB. "REGULATION OF LEUKOCYTE-ENDOTHELIUM INTERACTIONS THROUGH L-SELECTIN." JOURNAL OF LEUKOCYTE BIOLOGY (1993): 104-104.
Source
wos-lite
Published In
Journal of leukocyte biology
Publish Date
1993
Start Page
104
End Page
104

ELISA for quantitation of L-selectin shed from leukocytes in vivo.

L-selectin is a cell surface receptor on granulocytes, lymphocytes and monocytes that is responsible for the initial attachment of leukocytes to endothelium. The extracellular domain of L-selectin is proteolytically shed from leukocytes following cellular activation in vitro. The shed form of L-selectin (SL-selectin) is functionally active and at high concentrations can inhibit leukocyte attachment to endothelium. Therefore, an ELISA was developed to quantitate the levels of SL-selectin in biological fluids, biopsy specimens and during recombinant protein production. This simple, quantitative sandwich ELISA uses two monoclonal antibodies directed against the extracellular domain of SL-selectin. The assay has a detection range of 5-1300 ng/ml, is precise and sensitive. The ability of this assay to detect SL-selectin in serum, plasma, and culture supernatant fluid was demonstrated and it was used to quantitate circulating SL-selectin in normal and patient sera. Patients with sepsis and HIV infection showed markedly elevated SL-selectin levels in serum. Thus, the ELISA should prove useful both for laboratory purposes as well as in the diagnostic evaluation of patients with inflammatory diseases.

Authors
Spertini, O; Schleiffenbaum, B; White-Owen, C; Ruiz, P; Tedder, TF
MLA Citation
Spertini, O, Schleiffenbaum, B, White-Owen, C, Ruiz, P, and Tedder, TF. "ELISA for quantitation of L-selectin shed from leukocytes in vivo." J Immunol Methods 156.1 (November 25, 1992): 115-123.
PMID
1385536
Source
pubmed
Published In
Journal of Immunological Methods
Volume
156
Issue
1
Publish Date
1992
Start Page
115
End Page
123

Characterization of an Epstein-Barr virus receptor on human epithelial cells.

Epstein-Barr virus (EBV) adsorption to human B lymphocytes is mediated by the viral envelope glycoprotein, gp350/220, which binds to the cell surface protein, CD21, also known as the CR2 complement receptor. Human epithelial cells also express an EBV receptor. A candidate surface molecule of 195 kD has previously been identified on an epithelial cell line and explanted epithelial tissue by reactivity with the CD21 specific monoclonal antibody (mAb), HB-5a. In experiments to further characterize the epithelial cell EBV receptor, we have found that two human epithelial cell lines, RHEK-1 and HeLa, specifically bind intact EB virions. A 145-kD protein, similar in size to B lymphocyte CD21, was specifically precipitated from surface iodinated RHEK-1 cells using the HB-5a mAb, or using purified soluble gp350/220 coupled to agarose beads. The previously identified 195-kD protein did not bind to gp350/220 or react with two other anti-CD21 mAbs. CD21 homologous RNA, similar in size to the B lymphocyte CD21 mRNA, was detected in both RHEK-1 and HeLa cells. The nucleotide sequence of the epithelial cell cDNA was identical to B lymphocyte CD21. The longest clone differs from previously reported CD21 cDNAs in having additional 5' untranslated sequence. Polymerase chain reaction amplification of RHEK-1- or B lymphoblastoid-derived cDNA verified that most CD21 transcripts are initiated at least 30-50 nucleotides upstream of the previously reported mRNA cap site. These experiments demonstrate that human epithelial cells can express CD21, and that CD21 is likely to mediate EBV adsorption to epithelial cells.

Authors
Birkenbach, M; Tong, X; Bradbury, LE; Tedder, TF; Kieff, E
MLA Citation
Birkenbach, M, Tong, X, Bradbury, LE, Tedder, TF, and Kieff, E. "Characterization of an Epstein-Barr virus receptor on human epithelial cells." J Exp Med 176.5 (November 1, 1992): 1405-1414.
PMID
1383386
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
176
Issue
5
Publish Date
1992
Start Page
1405
End Page
1414

The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules.

CD19 is a member of the Ig superfamily expressed on the surface of B lymphocytes that may be involved in the regulation of B cell function. Immunoprecipitation studies with B cell lines solubilized by digitonin have shown CD19 to be part of a multimolecular complex that includes CD21 (CR2) and other unidentified proteins. In this study, two of the CD19-associated proteins were identified as TAPA-1, which is expressed on most cell types, and Leu-13, which is expressed on subsets of lymphoid cells. TAPA-1 and Leu-13 are physically associated in many cell lineages. CD19 and CD21 mAb each specifically coprecipitated proteins of the same size as those precipitated by TAPA-1 and Leu-13 mAb from B cell lines and cDNA-transfected K562 cell lines. Western blot analysis with a TAPA-1 mAb verified the identity of TAPA-1 in CD19 and CD21 immunoprecipitated materials. In addition, when TAPA-1 or Leu-13 were crosslinked and patched on the cell surface, all of the CD19 comigrated with TAPA-1 and some of the CD19 comigrated with Leu-13. Furthermore, mAb binding to CD19, CD21, TAPA-1, and Leu-13 on B cell lines induced similar biologic responses, including the induction of homotypic adhesion, inhibition of proliferation, and an augmentation of the increase in intracellular [Ca2+] induced by suboptimal cross-linking of surface Ig on B cell lines. Together, these data suggest that TAPA-1 and Leu-13 are broadly expressed members of a signal transduction complex in which lineage-specific proteins, such as CD19 and CD21, provide cell-specific functions.

Authors
Bradbury, LE; Kansas, GS; Levy, S; Evans, RL; Tedder, TF
MLA Citation
Bradbury, LE, Kansas, GS, Levy, S, Evans, RL, and Tedder, TF. "The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules." J Immunol 149.9 (November 1, 1992): 2841-2850.
PMID
1383329
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
149
Issue
9
Publish Date
1992
Start Page
2841
End Page
2850

Neutrophils, monocytes, and lymphocytes bind to cytokine-activated kidney glomerular endothelial cells through L-selectin (LAM-1) in vitro.

The role of L-selectin (LAM-1) as a regulator of leukocyte adhesion to kidney microvascular glomerular endothelial cells was assessed in vitro by using L-selectin-directed mAb and an L-selectin cDNA-transfected cell line. The initial attachment of neutrophils, monocytes, and lymphocytes to TNF-activated bovine glomerular endothelial cells was significantly inhibited by the anti-LAM1-3 mAb. Under static conditions, anti-LAM1-3 mAb inhibited neutrophil adhesion by 15 +/- 5%, whereas the anti-LAM1-10 mAb, directed against a functionally silent epitope of L-selectin, was without effect. The binding of a CD18 mAb inhibited adhesion by 47 +/- 6%. In contrast, when the assays were carried out under nonstatic conditions or at 4 degrees C, the anti-LAM1-3 mAb generated significantly greater inhibition (approximately 60%). CD18-dependent adhesion was minimal (approximately 10%) under these conditions. TNF-activated glomerular endothelial cells also supported adhesion of a mouse pre-B cell line transfected with L-selectin cDNA, but not wild-type cells. This process was also inhibited by the anti-LAM1-3 mAb. Leukocyte adhesion to unstimulated endothelial cells was independent of L-selectin, but, after TNF stimulation, L-selectin-mediated adhesion was observed at 4 h, with maximal induction persisting for 24 to 48 h. Leukocyte adhesion was not observed if glomerular endothelial cells were exposed to TNF in the presence of RNA or protein synthesis inhibitors. Leukocyte attachment to TNF-activated glomerular endothelial cells was also partially inhibited by treatment of the cells with mannose-6-phosphate or phosphomannan monoester, a soluble complex carbohydrate, or by prior treatment of glomerular endothelial cells with neuraminidase, suggesting that the glomerular endothelial cell ligand shares functional characteristics with those expressed by lymph node and large vessel endothelial cells. These data suggest that TNF activation induced the biosynthesis and surface expression of a ligand(s) for L-selectin on glomerular endothelial cells, which supports neutrophil, monocyte, and lymphocyte attachment under nonstatic conditions.

Authors
Brady, HR; Spertini, O; Jimenez, W; Brenner, BM; Marsden, PA; Tedder, TF
MLA Citation
Brady, HR, Spertini, O, Jimenez, W, Brenner, BM, Marsden, PA, and Tedder, TF. "Neutrophils, monocytes, and lymphocytes bind to cytokine-activated kidney glomerular endothelial cells through L-selectin (LAM-1) in vitro." J Immunol 149.7 (October 1, 1992): 2437-2444.
PMID
1382103
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
149
Issue
7
Publish Date
1992
Start Page
2437
End Page
2444

Soluble L-selectin is present in human plasma at high levels and retains functional activity.

L-selectin expressed by granulocytes, lymphocytes, and monocytes is responsible for initial leukocyte attachment to inflamed endothelium and high endothelial venules of peripheral lymph nodes. After leukocyte activation in vitro, L-selectin is rapidly shed from the cell surface. In this study, shed L-selectin (sL-selectin) from both lymphocytes and neutrophils was demonstrated to be present in high levels in human plasma by Western blot analysis and using a quantitative ELISA. In serum from normal human blood donors, a mean sL-selectin level of 1.6 +/- 0.8 micrograms/ml (n = 63) was found by ELISA. In addition, semipurified sL-selectin from plasma inhibited L-selectin-specific attachment of lymphocytes to cytokine-activated endothelium in a dose-dependent manner. L-selectin-dependent leukocyte attachment was completely inhibited at sL-selectin concentrations of 8-15 micrograms/ml, while physiological concentrations of sL-selectin caused a small but consistent inhibition of lymphocyte attachment. sL-selectin in plasma also inhibited anti-L-selectin mAb (2-5 micrograms/ml) binding to the surface of leukocytes. Interestingly, one epitope present within the EGF-like domain of L-selectin was lost in sL-selectin, suggesting a conformational change in the structure of the receptor after shedding. The presence of serum sL-selectin with functional activity indicates a potential role for sL-selectin in the regulation of leukocyte attachment to endothelium.

Authors
Schleiffenbaum, B; Spertini, O; Tedder, TF
MLA Citation
Schleiffenbaum, B, Spertini, O, and Tedder, TF. "Soluble L-selectin is present in human plasma at high levels and retains functional activity." J Cell Biol 119.1 (October 1992): 229-238.
PMID
1382078
Source
pubmed
Published In
The Journal of Cell Biology
Volume
119
Issue
1
Publish Date
1992
Start Page
229
End Page
238

A novel cell-surface molecule expressed by human interdigitating reticulum cells, Langerhans cells, and activated lymphocytes is a new member of the Ig superfamily.

cDNA isolated from a human lymphocyte library were analyzed and shown to encode a novel cell-surface glycoprotein, termed HB15, expressed by dendritic cell subsets and activated lymphocytes. The predicted mature 186 amino acid protein was composed of a single extracellular V-type Ig-like domain, a transmembrane region, and a 39-amino acid cytoplasmic domain. In contrast to most Ig-like domains, analysis of a partial genomic DNA clone revealed that the extracellular Ig-like domain of HB15 was encoded by at least two exons. Northern blot analysis revealed that HB15 derived from three mRNA transcripts of approximately 1.7, 2.0, and 2.5 kb expressed by lymphoblastoid cell lines. Two mAb reactive with HB15 were produced and used to show that HB15 is expressed as a single chain cell-surface glycoprotein of M(r) 45,000. HB15 expression was specific for lymphoblastoid cell lines and mitogen-activated lymphocytes, and HB15 was not expressed at detectable levels by circulating leukocytes. Immunohistologic analysis revealed that HB15 had a unique pattern of expression, being found predominantly in hemopoietic tissues with strong expression by scattered interfollicular interdigitating reticulum cells and weak expression by germinal center cells. HB15 was also expressed by Langerhans cells within the skin. HB15 therefore serves as a unique marker for the subset of dendritic cells represented by Langerhans cells and interdigitating reticulum cells. Thus, the HB15 glycoprotein represents a newly identified member of the Ig superfamily that may play a significant role in Ag presentation or the cellular interactions that follow lymphocyte activation.

Authors
Zhou, LJ; Schwarting, R; Smith, HM; Tedder, TF
MLA Citation
Zhou, LJ, Schwarting, R, Smith, HM, and Tedder, TF. "A novel cell-surface molecule expressed by human interdigitating reticulum cells, Langerhans cells, and activated lymphocytes is a new member of the Ig superfamily." J Immunol 149.2 (July 15, 1992): 735-742.
PMID
1378080
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
149
Issue
2
Publish Date
1992
Start Page
735
End Page
742

Monocyte attachment to activated human vascular endothelium in vitro is mediated by leukocyte adhesion molecule-1 (L-selectin) under nonstatic conditions.

The receptors that mediate monocyte adhesion to cytokine-stimulated endothelial monolayers were assessed using a nonstatic (rotating) cell-attachment assay. In this system, leukocyte adhesion molecule-1 (LAM-1) (L-selectin) mediated a major portion (87 +/- 15% at 37 degrees C) of monocyte attachment to activated endothelium. mAb blocking of endothelial leukocyte adhesion molecule-1 (41% inhibition), CD18 (36%), and vascular cell adhesion molecule-1 (25%) function had lesser effects on attachment. These results suggest that LAM-1 may serve an important role in monocyte attachment to endothelium at sites of inflammation.

Authors
Spertini, O; Luscinskas, FW; Gimbrone, MA; Tedder, TF
MLA Citation
Spertini, O, Luscinskas, FW, Gimbrone, MA, and Tedder, TF. "Monocyte attachment to activated human vascular endothelium in vitro is mediated by leukocyte adhesion molecule-1 (L-selectin) under nonstatic conditions." J Exp Med 175.6 (June 1, 1992): 1789-1792.
PMID
1375271
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
175
Issue
6
Publish Date
1992
Start Page
1789
End Page
1792

Tissue-specific migration pathways by phenotypically distinct subpopulations of memory T cells.

A proportion of T cells recirculate in a tissue-selective manner. Recent studies which showed that the skin-tropic subset of T cells was of memory/activated type, led us to examine whether the preferential homing of T cells to the gut also involved memory T cells, and if so whether these memory T cells were phenotypically distinct from other memory T cells. Lymphocytes migrating through the gut and the skin of sheep was collected by cannulating the lymphatic ducts draining these tissues. Both naive and memory T cells were found to recirculate through the gut, although only memory T cells migrated through the skin. However, when T cells from the gut were labeled with fluorescein isothiocyanate and assessed for their migration back to the gut, it was the memory population which showed a tropism for the gut. Gut-tropic memory T cells migrated poorly through the skin, indicating that these cells were distinct from skin-tropic memory T cells. This was confirmed by phenotypic analysis. Gut memory T cells expressed very low levels of the alpha 6 and beta 1 integrins, in contrast to skin memory T cells which expressed high levels. There was no evidence for heterogeneity within the naive T cell population, which migrated preferentially to lymph nodes. This migration pattern could be explained in part by the high expression of the L-selectin (lymph node homing receptor, LAM-1) on naive T cells, in contrast to memory T cells from gut or skin which were mostly L-selectin negative. These results in sheep indicate that subsets of alpha/beta memory T cells show tissue-selective migration patterns, which probably develop in a particular environment following encounter with antigen.

Authors
Mackay, CR; Marston, WL; Dudler, L; Spertini, O; Tedder, TF; Hein, WR
MLA Citation
Mackay, CR, Marston, WL, Dudler, L, Spertini, O, Tedder, TF, and Hein, WR. "Tissue-specific migration pathways by phenotypically distinct subpopulations of memory T cells." Eur J Immunol 22.4 (April 1992): 887-895.
PMID
1372559
Source
pubmed
Published In
European Journal of Immunology
Volume
22
Issue
4
Publish Date
1992
Start Page
887
End Page
895
DOI
10.1002/eji.1830220402

The B lymphocyte surface antigen CD75 is not an alpha-2,6-sialyltransferase but is a carbohydrate antigen, the production of which requires the enzyme.

Authors
Munro, S; Bast, BJ; Colley, KJ; Tedder, TF
MLA Citation
Munro, S, Bast, BJ, Colley, KJ, and Tedder, TF. "The B lymphocyte surface antigen CD75 is not an alpha-2,6-sialyltransferase but is a carbohydrate antigen, the production of which requires the enzyme." Cell 68.6 (March 20, 1992): 1003-. (Letter)
PMID
1547499
Source
pubmed
Published In
Cell
Volume
68
Issue
6
Publish Date
1992
Start Page
1003

CD4 binding to major histocompatibility complex class II antigens induces LFA-1-dependent and -independent homotypic adhesion of B lymphocytes.

T helper cells recognize processed antigen (Ag) in the context of major histocompatibility complex (MHC) class II antigens present on the surface of B cells and other Ag-presenting cells. This interaction is mediated through the T cell receptor complex with associate recognition of class II molecules by the CD4 molecule. In this study, the binding of a soluble recombinant CD4/Ig heavy chain fusion protein (CD4-gamma 3) or monoclonal antibody (mAb) to class II antigens on human B cells was shown to induce rapid and specific homotypic adhesion of B cells and most B lymphoblastoid cell lines. mAb reactive with CD4 inhibited CD4-gamma 3-induced adhesion and a mutant B lymphoblastoid cell line deficient in class II antigens failed to respond. Induction of homotypic adhesion was dependent on energy metabolism and a functional cytoskeleton, and class II+ pre-B cells did not exhibit adhesion in response to these stimuli, suggesting that cross-linking of class II molecules generated a transmembrane signal and did not simply aggregate cells. In addition, MHC class II-induced adhesion was Fc receptor independent, as 15 mAb of different Ig isotypes reactive with HLA-D or HLA-DQ gene products induced adhesion. Anti-class II mAb and CD4-gamma 3 were able to induce adhesion at concentrations as low as 10 ng/ml and 100 ng/ml, respectively. Suboptimal stimulation of B cell lines through HLA-D antigens induced homotypic adhesion that was dependent on the activation of LFA-1 (CD11a/CD18), and which could be blocked by specific mAb. However, at greater signal strengths, adhesion was not blocked by mAb against the known adhesion receptors, suggesting the induction of a novel adhesion pathway. Consistent with this, homotypic adhesion induced by engagement of MHC class II antigens was observed with LFA-1-deficient B cell lines, and was independent of CD49d or CD18 expression. Thus, the direct engagement of B cell class II antigens by CD4 is likely to generate transmembrane signals which trigger both LFA-1-dependent and LFA-1-independent adhesion pathways.

Authors
Kansas, GS; Cambier, JC; Tedder, TF
MLA Citation
Kansas, GS, Cambier, JC, and Tedder, TF. "CD4 binding to major histocompatibility complex class II antigens induces LFA-1-dependent and -independent homotypic adhesion of B lymphocytes." Eur J Immunol 22.1 (January 1992): 147-152.
PMID
1730248
Source
pubmed
Published In
European Journal of Immunology
Volume
22
Issue
1
Publish Date
1992
Start Page
147
End Page
152
DOI
10.1002/eji.1830220122

The HB-6, CDw75, and CD76 differentiation antigens are unique cell-surface carbohydrate determinants generated by the beta-galactoside alpha 2,6-sialyltransferase.

Expression of the beta-galactoside alpha 2,6-sialyltransferase (alpha 2,6-ST) was shown to regulate the generation of multiple cell-surface differentiation antigens (Ags) that may be necessary for lymphocyte function. A new mAb was produced, termed HB-6, that was shown to identify a novel neuraminidase-sensitive cell-surface Ag expressed by subpopulations of human lymphocytes and erythrocytes. In attempting to isolate a cDNA encoding the HB-6 antigen by expression cloning, a cDNA encoding the alpha 2,6-ST (EC 2.4.99.1) was obtained. Since expression of the alpha 2,6-ST protein was shown to be limited to the Golgi apparatus, the cell-surface HB-6 Ag was demonstrated to be the product of alpha 2,6-ST activity. Interestingly, alpha 2,6-ST expression also generated two other neuraminidase-sensitive lymphocyte cell-surface differentiation Ags, CDw75, and CD76. The HB-6, CDw75, and CD76 mAb identified distinct Ags that were differentially expressed by different B cell lines and exhibited different patterns of expression in tissue sections. These results indicate that alpha 2,6-ST expression is a critical regulatory step in the formation of the Ags that are recognized by these mAb, and that an alpha 2,6-linked sialic acid residue is an essential component of each Ag. Thus, expression of a single ST can result in the generation of multiple distinct antigenic determinants on the cell surface which can be distinguished by mAb and may have regulatory roles in lymphocyte function.

Authors
Bast, BJ; Zhou, LJ; Freeman, GJ; Colley, KJ; Ernst, TJ; Munro, JM; Tedder, TF
MLA Citation
Bast, BJ, Zhou, LJ, Freeman, GJ, Colley, KJ, Ernst, TJ, Munro, JM, and Tedder, TF. "The HB-6, CDw75, and CD76 differentiation antigens are unique cell-surface carbohydrate determinants generated by the beta-galactoside alpha 2,6-sialyltransferase." J Cell Biol 116.2 (January 1992): 423-435.
PMID
1730763
Source
pubmed
Published In
The Journal of Cell Biology
Volume
116
Issue
2
Publish Date
1992
Start Page
423
End Page
435

Structure of the genes encoding the CD19 antigen of human and mouse B lymphocytes.

CD19 is a B lymphocyte cell-surface marker that is expressed early during pre-B-cell differentiation with expression persisting until terminal differentiation into plasma cells. CD19 is a member of the Ig gene superfamily with two extracellular Ig-like domains separated by a non-Ig-like domain, and with an extensive approximately 240 amino acid cytoplasmic domain. In this study, Southern blot analysis revealed that the human and mouse CD19 genes were compact single copy genes. Both the human and mouse CD19 genes were isolated and the nucleotide sequences flanking each exon were determined. Both genes were composed of 15 exons and spanned approximately 8 kilobases (kb) of DNA in human and approximately 6 kb in mouse. The positions of exon-intron boundaries were identical between human and mouse and correlated with the putative functional domains of the CD19 protein. The 200 bp region 5' of the putative translation initiation AUG codon was well conserved in sequence between human and mouse and contained potential transcription regulatory elements. In addition, the 3' untranslated regions (UT) of the CD19 genes following the termination codon were conserved in sequence. The high level of conservation of nucleotide sequences between species in all exons and 5' and 3' UT suggests that expression of the CD19 gene may be regulated in a similar fashion in human and mouse.

Authors
Zhou, LJ; Ord, DC; Omori, SA; Tedder, TF
MLA Citation
Zhou, LJ, Ord, DC, Omori, SA, and Tedder, TF. "Structure of the genes encoding the CD19 antigen of human and mouse B lymphocytes." Immunogenetics 35.2 (1992): 102-111.
PMID
1370948
Source
pubmed
Published In
Immunogenetics
Volume
35
Issue
2
Publish Date
1992
Start Page
102
End Page
111

Transmembrane signals generated through MHC class II, CD19, CD20, CD39, and CD40 antigens induce LFA-1-dependent and independent adhesion in human B cells through a tyrosine kinase-dependent pathway.

Transmembrane signals generated following mAb binding to CD19, CD20, CD39, CD40, CD43, Leu-13 Ag, and HLA-D region gene products induced rapid and strong homotypic adhesion in a panel of human B cell lines. Lower levels of adhesion were also observed after engagement of CD21, CD22, and CD23. Adhesion induced by mAb binding to these Ag was identical with respect to the kinetics of adhesion and the morphology of the resulting cellular aggregates, and was distinct from PMA-induced adhesion in both of these properties. Adhesion was not observed in response to mAb binding to MHC class I, CD24, CD38, CD44, CD45RA, or CD72. In contrast to B cell lines, homotypic adhesion was not induced in two pre-B cell lines, in spite of their high level expression of CD19 and HLA-D. Adhesion induced by suboptimal stimulation through these surface Ag or by PMA was mediated primarily through LFA-1 and ICAM-1. However, optimal stimulation through CD19, CD20, CD39, CD40, and HLA-D induced strong homotypic adhesion that was not blocked by anti-LFA-1 mAb. This alternate pathway of adhesion was also observed in LFA-1-deficient cell lines and in the presence of EDTA, suggesting that adhesion was not mediated by integrins. Adhesion in response to engagement of cell-surface Ag was unaffected by H7 or genestein, but was significantly inhibited by staurosporine, and was completely ablated by sphingosine and herbimycin. These studies indicate that engagement of multiple B cell-surface molecules initiates a signal transduction cascade that involves tyrosine kinases but not protein kinase C, and which leads to homotypic adhesion. Furthermore, adhesion was mediated by at least two distinct cell-surface adhesion receptors: LFA-1/ICAM-1 and a heretofore unknown adhesion receptor.

Authors
Kansas, GS; Tedder, TF
MLA Citation
Kansas, GS, and Tedder, TF. "Transmembrane signals generated through MHC class II, CD19, CD20, CD39, and CD40 antigens induce LFA-1-dependent and independent adhesion in human B cells through a tyrosine kinase-dependent pathway." J Immunol 147.12 (December 15, 1991): 4094-4102.
PMID
1721639
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
147
Issue
12
Publish Date
1991
Start Page
4094
End Page
4102

Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion.

The human lymphocyte homing receptor, LAM-1, mediates the adhesion of lymphocytes to specialized high endothelial venules (HEV) of peripheral lymph nodes. We now report that LAM-1 is also a major mediator of leukocyte attachment to activated human endothelium. In a novel adhesion assay, LAM-1 was shown to mediate approximately 50% of the adhesion of both lymphocytes and neutrophils to TNF-activated human umbilical vein endothelial cells at 4 degrees C. The contribution of LAM-1 to leukocyte adhesion was only detectable when the assays were carried out under rotating (nonstatic) conditions, suggesting that LAM-1 is involved in the initial attachment of leukocytes to endothelium. In this assay at 37 degrees C, essentially all lymphocyte attachment to endothelium was mediated by LAM-1, VLA-4/VCAM-1, and the CD11/CD18 complex, whereas neutrophil attachment was mediated by LAM-1, endothelial-leukocyte adhesion molecule-1, and CD11/CD18. Thus, multiple receptors are necessary to promote optimal leukocyte adhesion to endothelium. LAM-1 also appeared to be involved in optimal neutrophil transendothelial migration using a videomicroscopic in vitro transmigration model system. LAM-1-dependent leukocyte adhesion required the induction and surface expression of a neuraminidase-sensitive molecule that was expressed for at least 24 h on activated endothelium. Expression of the LAM-1 ligand by endothelium was optimally induced by LPS and the proinflammatory cytokines TNF-alpha and IL-1 beta, whereas IFN-gamma and IL-4 induced lower levels of expression. The LAM-1 ligand on HEV and cytokine treated endothelium may be similar carbohydrate-containing molecules, because phosphomannan monoester core complex from yeast Hansenula hostii cell wall blocked binding of lymphocytes to both cell types, and identical epitopes on LAM-1-mediated lymphocyte attachment to HEV and activated endothelium. Thus, LAM-1 and its inducible endothelial ligand constitute a new pair of adhesion molecules that may regulate initial leukocyte/endothelial interactions at sites of inflammation.

Authors
Spertini, O; Luscinskas, FW; Kansas, GS; Munro, JM; Griffin, JD; Gimbrone, MA; Tedder, TF
MLA Citation
Spertini, O, Luscinskas, FW, Kansas, GS, Munro, JM, Griffin, JD, Gimbrone, MA, and Tedder, TF. "Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion." J Immunol 147.8 (October 15, 1991): 2565-2573.
PMID
1717567
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
147
Issue
8
Publish Date
1991
Start Page
2565
End Page
2573

Cell-surface receptor shedding: a means of regulating function.

Authors
Tedder, TF
MLA Citation
Tedder, TF. "Cell-surface receptor shedding: a means of regulating function." Am J Respir Cell Mol Biol 5.4 (October 1991): 305-306. (Review)
PMID
1654954
Source
pubmed
Published In
American journal of respiratory cell and molecular biology
Volume
5
Issue
4
Publish Date
1991
Start Page
305
End Page
306
DOI
10.1165/ajrcmb/5.4.305

Structure and domain organization of the CD19 antigen of human, mouse, and guinea pig B lymphocytes. Conservation of the extensive cytoplasmic domain.

The CD19 molecule is a 95,000 Mr cell-surface protein of human B lymphocytes with two extracellular Ig-like domains and a 240 amino acid cytoplasmic tail. cDNA encoding human CD19 and the cytoplasmic domain of the mouse CD19 Ag were previously isolated. In this report, those cDNA were used to isolate cDNA or genomic DNA encoding the complete mCD19 protein and a portion of CD19 from the guinea pig. Mouse pre-B and B cell lines expressed two CD19 mRNA species of 2.7 and 2.2 kb, whereas myeloma cell lines were negative as were T cell lines. Similarly, among mouse organs, only spleen contained detectable CD19 mRNA. These results suggest that only B cells express CD19 in mouse, as in man. Sequence determination revealed substantial conservation, with hCD19 and mCD19 being 66% and hCD19 and gpCD19 being 73% identical in amino acid sequence. The cytoplasmic region of CD19 was most highly conserved with human/mouse being 73% identical and human/guinea pig being 83% identical in amino acid sequence. Isolation of the hCD19 and mCD19 genes and determination of exon/intron boundaries revealed that both genes were structurally similar and were composed of at least 15 exons, 4 encoded extracellular domains, and 9 encoded cytoplasmic domains. Six of the exons that encoded cytoplasmic domains were essentially identical in sequence in all three species indicating that these regions have undergone considerable selective pressure to conserve sequences. Thus, CD19 appears to be well conserved in structure and expression through recent mammalian evolution and the highly conserved cytoplasmic domains may play a critical role in the transduction of CD19-mediated signals.

Authors
Zhou, LJ; Ord, DC; Hughes, AL; Tedder, TF
MLA Citation
Zhou, LJ, Ord, DC, Hughes, AL, and Tedder, TF. "Structure and domain organization of the CD19 antigen of human, mouse, and guinea pig B lymphocytes. Conservation of the extensive cytoplasmic domain." J Immunol 147.4 (August 15, 1991): 1424-1432.
PMID
1714482
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
147
Issue
4
Publish Date
1991
Start Page
1424
End Page
1432

Function and evolutionary conservation of distinct epitopes on the leukocyte adhesion molecule-1 (TQ-1, Leu-8) that regulate leukocyte migration.

The leukocyte adhesion molecule-1 (LAM-1, TQ=1, Leu-8) in humans, like its murine homologue, MEL-14, is the principal receptor that mediates the binding of leukocytes to high endothelial venules (HEV) of peripheral lymph nodes. In this study, several regions of the protein which mediate receptor function were identified by using a large panel of murine mAb reactive with LAM-1. Individual mAb reacted with LAM-1+ cells with characteristic intensities of immunofluorescence staining, and each bound both lymphocytes and neutrophils. Lymphocyte attachment to HEV was significantly inhibited by the binding of five mAb. In contrast, only two of these mAb were able to completely block the binding of phosphomannan monoester core complex from the yeast Hansenula holstii cell wall (PPME), a phosphomannan monoester core polysaccharide that serves as a soluble model of the natural ligand of LAM-1. Interestingly, the binding of two anti-LAM-1 mAb to cells induced a significant increase in PPME binding, reminiscent of the increase in receptor affinity observed after leukocyte activation. Antibody cross-blocking studies indicated that many of the functionally important epitopes were spatially distinct, and domain mapping indicated that they recognized distinct domains of LAM-1. The expression and function of these epitopes were further assessed by using a variety of animal species to further characterize the functionally relevant epitopes defined in these studies. At least some anti-LAM-1 mAb reacted with leukocytes from monkey, cow, rabbit, sheep, dog, cat, pig, and goat, but not from chicken, rat, or mouse. The reactivity of anti-LAM-1 mAb in several animal species correlated with the ability of leukocytes to bind PPME, and mAb that inhibited lymphocyte binding to HEV in man could also inhibit this function in rhesus monkey and dog. Thus, several LAM-1 epitopes are structurally and functionally well conserved throughout recent mammalian evolution, emphasizing an important role for LAM-1 in the regulation of leukocyte traffic.

Authors
Spertini, O; Kansas, GS; Reimann, KA; Mackay, CR; Tedder, TF
MLA Citation
Spertini, O, Kansas, GS, Reimann, KA, Mackay, CR, and Tedder, TF. "Function and evolutionary conservation of distinct epitopes on the leukocyte adhesion molecule-1 (TQ-1, Leu-8) that regulate leukocyte migration." J Immunol 147.3 (August 1, 1991): 942-949.
PMID
1713609
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
147
Issue
3
Publish Date
1991
Start Page
942
End Page
949

Molecular mapping of functional domains of the leukocyte receptor for endothelium, LAM-1.

The human lymphocyte homing receptor LAM-1, like its murine counterpart MEL-14, functions as a mammalian lectin, and mediates the binding of leukocytes to specialized high endothelial cells in lymphoid organs (HEV). LAM-1 is a member of a new family of cell adhesion molecules, termed selectins or LEC-CAMs, which also includes ELAM-1 and PAD-GEM (GMP-140/CD62). To localize the regions of LAM-1 that are involved in cell adhesion, we developed chimeric selectins, in which various domains of PAD-GEM were substituted into LAM-1, and used these chimeric proteins to define the domain requirements for carbohydrate binding, and to localize the regions recognized by several mAb which inhibit the adhesion of lymphocytes to lymph node HEV. The binding of PPME or fucoidin, soluble complex carbohydrates that specifically define the lectin activity of LAM-1 and MEL-14, required only the lectin domain of LAM-1. The LAM1-1, LAM1-3, and LAM1-6 mAb each strongly inhibit the binding of lymphocytes to HEV in the in vitro frozen section assay, and defined three independent epitopes on LAM-1. Blocking of PPME or fucoidin binding by LAM1-3 indicated that this site is identical, or in close proximity, to the carbohydrate binding site, and analysis of the binding of LAM1-3 to chimeric selectins showed that the epitope detected by LAM1-3 is located within the lectin domain. Although the LAM1-6 epitope is also located in the lectin domain, LAM1-6 did not affect the binding of PPME or fucoidin. The LAM1-1 epitope was located in, or required, the EGF domain, and, importantly, binding of LAM1-1 significantly enhanced the binding of both PPME and fucoidin. These results suggest that adhesion mediated by LAM-1 may involve cooperativity between functionally and spatially distinct sites, and support previous data suggesting a role for the EGF domain of LAM-1 in lymphocyte adhesion to HEV.

Authors
Kansas, GS; Spertini, O; Stoolman, LM; Tedder, TF
MLA Citation
Kansas, GS, Spertini, O, Stoolman, LM, and Tedder, TF. "Molecular mapping of functional domains of the leukocyte receptor for endothelium, LAM-1." J Cell Biol 114.2 (July 1991): 351-358.
PMID
1712791
Source
pubmed
Published In
The Journal of Cell Biology
Volume
114
Issue
2
Publish Date
1991
Start Page
351
End Page
358

Expression, distribution, and biochemistry of human CD39. Role in activation-associated homotypic adhesion of lymphocytes.

The distribution, biochemical properties, and function of CD39 were characterized with the use of a new mAb termed 400. CD39 is an acidic (isoelectric point, approximately 4.2) glycoprotein of Mr approximately 78,000, containing approximately 24 kDa of N-linked oligosaccharide but no detectable O-linked sugars. CD39 was not expressed by resting blood T, B, or NK cells, neutrophils, or monocytes, but was expressed on activated NK cells, B cells, subsets of T cells, and T cell clones. Furthermore, the pattern of expression of CD39 was distinct from the "classic" activation Ag CD25 and CD71, inasmuch as it was expressed long after expression of CD25 and CD71 had returned to basal levels. CD39 was easily detectable on EBV-transformed B cell lines but was absent from pre-B and non-EBV-transformed B cell lines, most myeloid cell lines, and leukemic T cell lines. In lymphoid tissues, germinal center cells expressed little or no CD39, whereas some paracortical lymphocytes and most macrophages and dendritic cells were positive. CD39 was strongly expressed by endothelium in all tissues examined, including skin, and was present on some, but not all, endothelial cell lines propagated in vitro. Interestingly, mAb binding to certain epitopes on CD39 induced rapid homotypic adhesion that appeared to involve LFA-1 (CD11a/CD18), but was morphologically and kinetically distinct from that induced by PMA. Anti-CD39 mAb also induced homotypic adhesion in an CD11/CD18-EBV-transformed B cell line derived from a patient with severe leukocyte adhesion deficiency. This adhesion was unaffected by EDTA, suggesting that this pathway of anti-CD39-induced homotypic adhesion was not mediated by any of the known integrins. These studies suggest that CD39 is involved in the cellular signaling that regulates adhesion.

Authors
Kansas, GS; Wood, GS; Tedder, TF
MLA Citation
Kansas, GS, Wood, GS, and Tedder, TF. "Expression, distribution, and biochemistry of human CD39. Role in activation-associated homotypic adhesion of lymphocytes." J Immunol 146.7 (April 1, 1991): 2235-2244.
PMID
1672348
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
146
Issue
7
Publish Date
1991
Start Page
2235
End Page
2244

Regulation of leukocyte adhesion molecule-1 (TQ1, Leu-8) expression and shedding by normal and malignant cells.

The human leukocyte adhesion molecule-1 (LAM-1, TQ1, Leu-8) is involved in the binding of human leukocytes to high endothelial venules (HEV) of peripheral lymph nodes (LN). The regulation of LAM-1 expression is unique in that leukocyte stimulation induces a rapid down-modulation of LAM-1 from the cell surface. In this study, the regulation and function of LAM-1 was studied in detail in normal lymphocytes and compared with the LAM-1 of malignant leukocytes. Modulation of LAM-1 from the cell surface occurred concomitantly with the appearance of LAM-1 in the culture medium indicating that LAM-1 is cleaved from the cell surface. Shedding of LAM-1 was decreased in the presence of protein kinase C (PKC) inhibitors. As with normal lymphocytes, cells transfected with the LAM-1 cDNA and chronic lymphocytic leukemia (CLL) cells also shed LAM-1 following phorbol myristate acetate (PMA) exposure. CLL cells expressed the same Mr LAM-1 protein as normal lymphocytes and LAM-1+ CLL cells were able to specifically bind to HEV. In addition, normal lymphocytes and LAM-1+ CLL cells were capable of binding polyphosphomonester core polysaccharide (PPME) derived from yeast cell wall, a carbohydrate which mimics an essential component of the natural ligand for LAM-1, and PPME and HEV binding was specifically blocked by a new monoclonal antibody (mAb) reactive with LAM-1. The expression of LAM-1 and other adhesion molecules was examined on cells of 118 hematopoietic malignancies. LAM-1 was most frequently expressed on CLL and follicular or diffuse small cleaved cell lymphomas, whereas most other malignancies were LAM-1-. Thus, most CLL cells and some non-Hodgkin's lymphoma cells express a functionally active LAM-1 molecule which may correlate with their capacity to migrate through the circulation and disseminate into peripheral LN.

Authors
Spertini, O; Freedman, AS; Belvin, MP; Penta, AC; Griffin, JD; Tedder, TF
MLA Citation
Spertini, O, Freedman, AS, Belvin, MP, Penta, AC, Griffin, JD, and Tedder, TF. "Regulation of leukocyte adhesion molecule-1 (TQ1, Leu-8) expression and shedding by normal and malignant cells." Leukemia 5.4 (April 1991): 300-308.
PMID
1709244
Source
pubmed
Published In
Leukemia
Volume
5
Issue
4
Publish Date
1991
Start Page
300
End Page
308

Regulation of leukocyte migration by activation of the leukocyte adhesion molecule-1 (LAM-1) selectin.

A central feature of host defence is the ability of leukocytes to enter tissues in response to immune or inflammatory stimuli. The leukocyte adhesion molecule-1 (LAM-1) regulates the migration of human leukocytes by mediating the binding both of lymphocytes to high endothelial venules of peripheral lymph nodes and of neutrophils to endothelium at inflammatory sites. As lymphocytes and neutrophils express the same LAM-1 protein, it is not clear how lineage-specific differences in leukocyte migration are controlled. We now report that the affinity of LAM-1 for a carbohydrate-based ligand, PPME, is dramatically increased following lymphocyte and neutrophil activation by lineage-specific stimuli. In addition, activation of lymphocytes by physiological stimuli enhanced LAM-1-dependent binding to high endothelial venules. Thus, transient changes in LAM-1 affinity after leukocyte stimulation probably directly influence leukocyte migration.

Authors
Spertini, O; Kansas, GS; Munro, JM; Griffin, JD; Tedder, TF
MLA Citation
Spertini, O, Kansas, GS, Munro, JM, Griffin, JD, and Tedder, TF. "Regulation of leukocyte migration by activation of the leukocyte adhesion molecule-1 (LAM-1) selectin." Nature 349.6311 (February 21, 1991): 691-694.
PMID
1705015
Source
pubmed
Published In
Nature
Volume
349
Issue
6311
Publish Date
1991
Start Page
691
End Page
694
DOI
10.1038/349691a0

Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19.

The complement system augments the humoral immune response, possibly by a mechanism that involves the B lymphocyte membrane receptor, CR2, which binds the C3dg fragment of C3 and triggers several B cell responses in vitro. The present study demonstrates that CR2 associates with a complex of membrane proteins that may mediate signal transduction by ligated CR2. Monoclonal antibodies to CR2 immunoprecipitated from digitonin lysates of Raji B lymphoblastoid cells a membrane complex containing CR2, approximately equimolar amounts of CD19, which is a member of the immunoglobulin superfamily, and three unidentified components: p130, p50, and p20. The complex, which was immunoprecipitated also with anti-CD19, could be dissociated by Nonidet P-40, accounting for its absence in previous studies of CR2. Expression of recombinant CR2 and CD19 in K562 erythroleukemia cells led to formation of a complex that contained not only these two proteins but also p130, p50, and p20, and another component, p14. These unidentified components of the CR2/CD19 complex coimmunoprecipitated with CD19 and not with CR2 from singly transfected cells, indicating primary association with the former. CD19 replicated the capacity of CR2 to interact synergistically with mIgM for increasing free intracellular Ca2+, suggesting that the complex mediates this function of CR2. Therefore, CR2 associates directly with CD19 to become a ligand-binding subunit of a pre-existing signal transduction complex of the B cell that may be representative of a family of membrane protein complexes. This interaction between the complement and immune systems differs from that between immunoglobulin and Clq by involving membrane rather than plasma proteins, and by having complement involved in the afferent phase of the immune response.

Authors
Matsumoto, AK; Kopicky-Burd, J; Carter, RH; Tuveson, DA; Tedder, TF; Fearon, DT
MLA Citation
Matsumoto, AK, Kopicky-Burd, J, Carter, RH, Tuveson, DA, Tedder, TF, and Fearon, DT. "Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19." J Exp Med 173.1 (January 1, 1991): 55-64.
PMID
1702139
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
173
Issue
1
Publish Date
1991
Start Page
55
End Page
64

Selectins: A family of adhesion receptors

Authors
Bevilacqua, M; Butcher, E; Furie, B; Furie, B; Gallatin, M; Gimbrone, M; Harlan, J; Kishimoto, K; Lasky, L; McEver, R; Paulson, J; Rosen, S; Seed, B; Siegelman, M; Springer, T; Stoolman, L; Tedder, T; Varki, A; Wagner, D; Weissman, I; Zimmerman, G
MLA Citation
Bevilacqua, M, Butcher, E, Furie, B, Furie, B, Gallatin, M, Gimbrone, M, Harlan, J, Kishimoto, K, Lasky, L, McEver, R, Paulson, J, Rosen, S, Seed, B, Siegelman, M, Springer, T, Stoolman, L, Tedder, T, Varki, A, Wagner, D, Weissman, I, and Zimmerman, G. "Selectins: A family of adhesion receptors." Cell 67.2 (1991): 233--.
PMID
1717161
Source
scival
Published In
Cell
Volume
67
Issue
2
Publish Date
1991
Start Page
233-
DOI
10.1016/0092-8674(91)90174-W

Granulocyte-macrophage colony-stimulating factor and other cytokines regulate surface expression of the leukocyte adhesion molecule-1 on human neutrophils, monocytes, and their precursors.

There is increasing evidence that cytokines such as granulocyte-macrophage (GM)-CSF can profoundly affect the adhesion, aggregation, and mobility of neutrophils both in vitro and in vivo. However, the mechanisms whereby these factors might alter the adhesive properties of neutrophils are incompletely understood. A new family of cellular adhesion molecules has recently been identified by cDNA cloning. The members of this family include human leukocyte adhesion molecule-1 (LAM-1), the human endothelial-leukocyte adhesion molecule, and the mouse leukocyte homing receptor for high endothelial venules, MEL-14. LAM-1 is the human homologue of murine MEL-14, and is believed to mediate binding of leukocytes to human high endothelial venules. LAM-1 can be identified by mAb TQ-1, Leu 8, or anti-LAM1.1. The expression and regulation of LAM-1 on granulocytes, monocytes, and their precursors was investigated using flow cytometry and the anti-LAM-1.1 mAb. Neutrophils, eosinophils, monocytes, marrow myeloid cells, granulocyte/macrophage colony-forming unit, and burst-forming unit for erythroid cells were LAM-1+ by flow microfluorimetry. The regulation of LAM-1 expression was tested by treating various cell populations with cytokines or other stimuli for 0-90 min. Exposure of neutrophils, monocytes, and marrow myeloid cells to GM-CSF induced rapid and complete loss of LAM-1 from the cell surface, but had no effect on LAM-1 expression by lymphocytes. The loss of LAM-1 was temporally correlated with up-regulation of CD11b (Mo1), an adhesion molecule involved in neutrophil aggregation. Several other factors known to activate neutrophils also caused down-regulation of LAM-1 and up-regulation of CD11b, including TNF, FMLP, and leukotriene B4. Interestingly, granulocyte-CSF and IFN-gamma had minimal effects on neutrophil LAM-1 expression. Similar results were observed on monocytes and myeloid precursor cells. Thus, exposure of neutrophils to GM-CSF results in a profound change in surface expression of adhesion molecules, with coordinated up-regulation of CD11b and down-regulation of LAM-1. These changes in adhesion proteins are likely to alter aggregation and mobility of both mature myeloid cells and their precursors in patients receiving certain types of cytokine therapy.

Authors
Griffin, JD; Spertini, O; Ernst, TJ; Belvin, MP; Levine, HB; Kanakura, Y; Tedder, TF
MLA Citation
Griffin, JD, Spertini, O, Ernst, TJ, Belvin, MP, Levine, HB, Kanakura, Y, and Tedder, TF. "Granulocyte-macrophage colony-stimulating factor and other cytokines regulate surface expression of the leukocyte adhesion molecule-1 on human neutrophils, monocytes, and their precursors." J Immunol 145.2 (July 15, 1990): 576-584.
PMID
1694883
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
145
Issue
2
Publish Date
1990
Start Page
576
End Page
584

Evolution of the MHC class I genes of a New World primate from ancestral homologues of human non-classical genes.

The products of the classical human major histocompatibility complex (MHC) class I genes (HLA-A, -B, -C) are highly polymorphic molecules that bind peptides and present them to T lymphocytes. The non-polymorphic, non-classical MHC class I gene products (HLA-E, -F, -G) are not restricting elements for the majority of T lymphocytes. The evolutionary relationship of the non-classical and classical MHC class I genes is unclear. Here we present the cloning and sequencing of the MHC class I genes of a New World primate, the cotton-top tamarin (Saguinus oedipus). The expressed MHC class I genes of this species are more closely related to the human non-classical HLA-G gene than they are to genes of the human classical HLA-A, -B, and -C loci. These observations imply that classical and non-classical genes do not necessarily constitute mutually exclusive groups over evolutionary time.

Authors
Watkins, DI; Chen, ZW; Hughes, AL; Evans, MG; Tedder, TF; Letvin, NL
MLA Citation
Watkins, DI, Chen, ZW, Hughes, AL, Evans, MG, Tedder, TF, and Letvin, NL. "Evolution of the MHC class I genes of a New World primate from ancestral homologues of human non-classical genes." Nature 346.6279 (July 5, 1990): 60-63.
PMID
2114550
Source
pubmed
Published In
Nature
Volume
346
Issue
6279
Publish Date
1990
Start Page
60
End Page
63
DOI
10.1038/346060a0

Combined immunodeficiency due to the selective absence of CD4 inducer T lymphocytes.

Selective congenital deficiency of the CD4 inducer T lymphocyte subset is a recently described variant of combined immunodeficiency. To further characterize the cellular and molecular mechanisms which lead to the profound T and B cell immunodeficiency in this condition, we examined in vitro immunoregulatory T lymphocyte activation and effector function, interleukin-2 (IL-2) synthesis, IL-2 receptor generation, and CD4 gene structure. Immunophenotyping of T lymphocytes demonstrated a selective deficiency of CD4+ cells, with normal numbers of CD2+ and CD3+ T cells, nearly all of which expressed the CD8+ determinant. Mitogen- and alloantigen-induced blastogenesis was profoundly decreased. B lymphocytes were present in normal numbers but there was a functional dysgammaglobulinemia (low IgG, normal IgM, low IgA) with no antibody response to in vivo immunization. T cells from the patient did not provide help to normal B cells for in vitro immunoglobulin synthesis; however, the patient's B cells were capable of synthesizing normal amounts of IgG when provided help from normal T cells. Concanavalin A failed to activate suppressor-inducer function in the patient's T cells. However, CD8+ T cell-mediated suppression was expressed if the patients T cells were cocultured with normal CD4+ T cells in a pokeweed mitogen-stimulated IgG secretion assay. IL-2 secretion and IL-2 receptor expression were both markedly reduced. Southern blot analysis of genomic DNA revealed no obvious abnormality in CD4 gene structure. The global defects in T cell activation, effector function, immunoregulation, and lymphokine generation observed in CD4+ inducer lymphocyte deficiency emphasizes the central role that the CD4 T lymphocyte plays in the activation and regulation in vivo immune responses.

Authors
Sleasman, JW; Tedder, TF; Barrett, DJ
MLA Citation
Sleasman, JW, Tedder, TF, and Barrett, DJ. "Combined immunodeficiency due to the selective absence of CD4 inducer T lymphocytes." Clinical immunology and immunopathology 55.3 (June 1990): 401-417.
PMID
1971201
Source
epmc
Published In
Clinical Immunology and Immunopathology
Volume
55
Issue
3
Publish Date
1990
Start Page
401
End Page
417
DOI
10.1016/0090-1229(90)90127-c

Human antigen-specific memory T cells express the homing receptor (LAM-1) necessary for lymphocyte recirculation.

Lymphocytes must circulate from blood into lymphoid tissues and sites of infection and inflammation to function efficiently in vivo. This process of "homing" is in part directed by the expression of the leukocyte adhesion molecule (LAM-1, also known as TQ1 and Leu-8) in humans and the homologous MEL-14 antigen in mice. In this report, we demonstrate that the LAM-1 molecule is a 74-kDa protein and that only half of the CD4+ T cells in humans which have a memory phenotype (CD45RA -CD29hi) express the LAM-1 molecule. Functionally, these two phenotypically distinct subpopulations of memory cells were quite different. The LAM-1+ memory cells proliferated better to recall antigen and induced three to seven times higher levels of B cell immunoglobulin secretion than their LAM-1- counterparts. Thus, antigen-specific memory T cells within the helper lineage express the homing receptor appropriate for regulating their migration to secondary lymphoid tissues and sites of inflammation.

Authors
Tedder, TF; Matsuyama, T; Rothstein, D; Schlossman, SF; Morimoto, C
MLA Citation
Tedder, TF, Matsuyama, T, Rothstein, D, Schlossman, SF, and Morimoto, C. "Human antigen-specific memory T cells express the homing receptor (LAM-1) necessary for lymphocyte recirculation." Eur J Immunol 20.6 (June 1990): 1351-1355.
PMID
1695155
Source
pubmed
Published In
European Journal of Immunology
Volume
20
Issue
6
Publish Date
1990
Start Page
1351
End Page
1355
DOI
10.1002/eji.1830200622

The role of functionally distinct helper T lymphocyte subpopulations in the induction of human B cell differentiation.

Human helper T lymphocytes can be dissected into two functionally distinct subpopulations based on expression of the CD45RA (2H4) or CD45R0 (UCHL-1) surface antigens. While both subpopulations are able to induce equivalent levels of B cell activation and proliferation, only the CD4+CD45RA- subpopulation is capable of inducing B cell differentiation in pokeweed mitogen (PWM)-stimulated cultures. To define the mechanism responsible for the dichotomy between induction of proliferation and differentiation by the two CD4+ subpopulations, we examined the abilities of the purified T cell subpopulations to produce lymphokine mRNA following T cell activation. Northern analysis revealed that both subpopulations produced interleukin (IL) 2 and interferon (IFN)-gamma mRNA following PWM activation. The CD4+CD45RA- subpopulation, however, produced higher levels of IFN-gamma mRNA and the CD4+CD45RA+ cells produced higher levels of IL 2 mRNA. Neither subpopulation elaborated detectable mRNA for IL 4, IL 5 or IL 6. Of greatest significance was that the addition of recombinant or T cell-derived lymphokines could not compensate for the inability of the CD4+CD45RA+ subpopulation to induce B cell differentiation in PWM assays. Direct T-B cell contact was required for the optimal induction B cell differentiation in these assays, suggesting that CD4+CD45RA+ T cells were deficient in their ability to directly deliver the T cell-B cell signals required for B cell differentiation. These results suggest that the differential ability of the two subpopulations of CD4+ T cells to induce B cell differentiation does not result from differences in lymphokines elaborated, but may result from differences in their abilities to interact directly with B cells to initiate differentiation.

Authors
Sleasman, JW; Morimoto, C; Schlossman, SF; Tedder, TF
MLA Citation
Sleasman, JW, Morimoto, C, Schlossman, SF, and Tedder, TF. "The role of functionally distinct helper T lymphocyte subpopulations in the induction of human B cell differentiation." European journal of immunology 20.6 (June 1990): 1357-1366.
PMID
1973388
Source
epmc
Published In
European Journal of Immunology
Volume
20
Issue
6
Publish Date
1990
Start Page
1357
End Page
1366
DOI
10.1002/eji.1830200623

Structure of the gene encoding the human leukocyte adhesion molecule-1 (TQ1, Leu-8) of lymphocytes and neutrophils.

The leukocyte adhesion molecule-1 (LAM-1, TQ1, Leu-8), expressed by human lymphocytes, neutrophils, monocytes, and their precursors, is a member of the selectin family of cellular adhesion/homing receptors which play important roles in leukocyte-endothelial cell interactions. These cell surface molecules contain an amino-terminal lectin-like domain followed by an epidermal growth factor-like domain and a variable number of short consensus repeat sequences similar to those found in C3/C4 binding proteins. In this report, the structure of the lyam-1 gene that encodes the LAM-1 protein was determined by isolating overlapping genomic DNA clones that hybridized with a LAM-1 cDNA probe. The lyam-1 gene spans greater than 30 kilo base pairs of DNA and is composed of at least 10 exons. The 5' end of the LAM-1 mRNA was mapped by primer extension analysis revealing a single initiation region for transcription. Exons II through X contain translated sequences; exon II encodes the translation initiation codon; exon III, the leader peptide; IV, the lectin-like domain; V, the epidermal growth factor-like domain; VI and VII, the short consensus repeat units; exon VIII, the transmembrane region; exon IX encodes seven amino acids containing a potential phosphorylation site; and exon X encodes the five remaining amino acids of the cytoplasmic tail and the long 3' untranslated region. Sequencing of LAM-1 cDNA clones derived from neutrophils revealed that the protein expressed by neutrophils would be identical in sequence with the protein expressed by lymphocytes and cDNAs that would encode different isoforms of LAM-1 protein were not detected. In addition, the level of LAM-1 expression by lymphocytes and neutrophils from two patients with paroxysmal nocturnal hemoglobinuria, a disorder in which linkage of phosphatidylinositol anchors to proteins is defective, was similar to that of normal controls. Therefore, the usage of exons II through X results in the generation of a single major LAM-1 protein product expressed by lymphocytes and neutrophils.

Authors
Ord, DC; Ernst, TJ; Zhou, LJ; Rambaldi, A; Spertini, O; Griffin, J; Tedder, TF
MLA Citation
Ord, DC, Ernst, TJ, Zhou, LJ, Rambaldi, A, Spertini, O, Griffin, J, and Tedder, TF. "Structure of the gene encoding the human leukocyte adhesion molecule-1 (TQ1, Leu-8) of lymphocytes and neutrophils." J Biol Chem 265.14 (May 15, 1990): 7760-7767.
PMID
1692315
Source
pubmed
Published In
The Journal of biological chemistry
Volume
265
Issue
14
Publish Date
1990
Start Page
7760
End Page
7767

Molecular cloning of cDNA that encode MHC class I molecules from a New World primate (Saguinus oedipus). Natural selection acts at positions that may affect peptide presentation to T cells.

To investigate the evolutionary pressures that drive the generation of polymorphism in primate MHC class I molecules, three cDNA that encode MHC class I alleles from a New World monkey, the cotton-top tamarin (Saguinus oedipus), were cloned and sequenced. These tamarin MHC class I alleles contained amino acid substitutions not found in any of the previously sequenced human MHC class I alleles. Moreover, the majority of these unique amino acid substitutions was located in the Ag recognition site at positions that have been shown to be critical in the presentation of viral peptides to T cells in mice and humans. These data suggest that selective pressures on MHC class I molecules preferentially act on the Ag recognition site and that the peptide binding or presenting functions of these molecules may drive the generation of MHC class I polymorphism. The novel Ag recognition sites of the tamarin MHC class I molecules, in addition to their restricted polymorphism, might account for the unusual susceptibility of the cotton-top tamarin to human pathogens.

Authors
Watkins, DI; Letvin, NL; Hughes, AL; Tedder, TF
MLA Citation
Watkins, DI, Letvin, NL, Hughes, AL, and Tedder, TF. "Molecular cloning of cDNA that encode MHC class I molecules from a New World primate (Saguinus oedipus). Natural selection acts at positions that may affect peptide presentation to T cells." J Immunol 144.3 (February 1, 1990): 1136-1143.
PMID
2104912
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
144
Issue
3
Publish Date
1990
Start Page
1136
End Page
1143

Expression of the human leukocyte adhesion molecule, LAM1. Identity with the TQ1 and Leu-8 differentiation antigens.

The LAM1 molecule is a member of the new family of cellular adhesion/homing molecules that contain a lectin-like domain at their amino-terminal end followed by an epidermal growth factor-like domain and short consensus repeat units like those found in C3/C4 binding proteins. Two mAb that react with the leukocyte adhesion molecule 1 (LAM1) were produced and used to examine the cell-surface expression of LAM1. The anti-LAM1 antibodies were reactive with the majority of blood lymphocytes, NK cells, neutrophils, and monocytes. LAM1 was also expressed by subpopulations of phenotypically immature and mature thymocytes. Blood lymphocytes rapidly modulated LAM1 from the cell surface during PMA exposure for 60 min. Coordinate with the loss of LAM1 from the cell surface, PMA-treated lymphocytes lost the ability to bind to lymph node high endothelial venules, indicating that expression of LAM1 may play a role in lymphocyte homing. Mitogen stimulation of blood T and B lymphocytes also resulted in decreased LAM1 expression, but at a slower rate. LAM1 was only weakly expressed by a minority of spleen lymphocytes. However, culturing spleen lymphocytes in media alone resulted in increased expression of LAM1 by a subpopulation of the cells (40 to 60%). Concomitant mitogen stimulation of spleen lymphocytes resulted initially in down-regulation of LAM1 expression followed by increased expression of LAM1 and then subsequent loss of LAM1 from the cell surface. The pattern of anti-LAM1 antibody reactivity was identical to that reported for the TQ1 and Leu-8 antibodies, and all of these antibodies reacted with cells transfected with the LAM1 cDNA. Thus, LAM1 is broadly expressed by leukocytes, and binding of LAM1 may participate in the process of leukocyte extravasation into lymphoid organs or sites of acute inflammation with subsequent loss of LAM1 from the cell surface.

Authors
Tedder, TF; Penta, AC; Levine, HB; Freedman, AS
MLA Citation
Tedder, TF, Penta, AC, Levine, HB, and Freedman, AS. "Expression of the human leukocyte adhesion molecule, LAM1. Identity with the TQ1 and Leu-8 differentiation antigens." J Immunol 144.2 (January 15, 1990): 532-540.
PMID
1688580
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
144
Issue
2
Publish Date
1990
Start Page
532
End Page
540

A frequent human CD20 (B1) differentiation antigen DNA polymorphism detected with MspI is located near 11q12-13.

Authors
Charmley, P; Nguyen, J; Tedder, TF; Gatti, RA
MLA Citation
Charmley, P, Nguyen, J, Tedder, TF, and Gatti, RA. "A frequent human CD20 (B1) differentiation antigen DNA polymorphism detected with MspI is located near 11q12-13." Nucleic Acids Res 18.1 (January 11, 1990): 207-.
PMID
1689820
Source
pubmed
Published In
Nucleic Acids Research
Volume
18
Issue
1
Publish Date
1990
Start Page
207

Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily.

The CD19 (B4) molecule is a m.w. 95,000 cell-surface protein of human B lymphocytes that is expressed before Ig and persists throughout differentiation. In this report, cDNA clones that encode the CD19 molecule were isolated and the amino acid sequence of CD19 was determined. A cDNA clone that selectively hybridized to RNA from CD19+ cell lines was selected from a human tonsilar cDNA library using differential hybridization. This cDNA was used to isolate additional cDNA clones. Four of the five longest cDNA clones isolated were sequenced and found to contain unique sequences presumed to be introns. One clone, pB4-19, was near full length (2.1 kb) and did not contain these putative introns. pB4-19 contained an 1685 bp open reading frame that could encode a protein of about 60 kDa. COS cells that were transfected with pB4-19 expressed a nascent cell surface structure reactive with the anti-B4 antibody. Immunoprecipitation of this structure from surface-iodinated COS cells with the anti-B4 antibody revealed a m.w. 85,000 protein. Northern blot analysis indicated that pB4-19 hybridized with a predominant mRNA species of 2.4 kb and a minor species of 1.5 kb, found in only CD19+ cells. The pre-B cell line, PB-697, also expressed four larger RNA species that hybridized with pB4-19. cDNA clones that encode the putative cytoplasmic portion (247 amino acids) of the mouse CD19 molecule were also isolated and found to be highly homologous (79 and 75%) with the human CD19 nucleotide and amino acid sequences. The deduced amino acid sequence of the CD19 cytoplasmic tail shared no significant homology with other known proteins but the putative extracellular region contained two Ig-like domains indicating that CD19 is a new member of the Ig superfamily.

Authors
Tedder, TF; Isaacs, CM
MLA Citation
Tedder, TF, and Isaacs, CM. "Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily." J Immunol 143.2 (July 15, 1989): 712-717.
PMID
2472450
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
143
Issue
2
Publish Date
1989
Start Page
712
End Page
717

Isolation and chromosomal localization of cDNAs encoding a novel human lymphocyte cell surface molecule, LAM-1. Homology with the mouse lymphocyte homing receptor and other human adhesion proteins.

A cDNA encoding a new human lymphocyte cell surface molecule has been isolated and shown to identify a fourth member of a recently discovered family of adhesion proteins. This lymphocyte-associated molecule (LAM-1) is uniquely composed of multiple distinct domains, one domain homologous with animal lectins, one homologous with epidermal growth factor, and two short consensus repeat units similar to those found in C3/C4 binding proteins. This cDNA clone hybridized with RNAs found in B cell lines and T lymphocytes, but not with RNA from other cell types. The amino acid sequence of LAM-1 is 77% homologous with the sequence of the mouse lymphocyte homing receptor, suggesting that LAM-1 may function in human lymphocyte adhesion. The LAM-1 gene is located on chromosome 1q23-25, as is another member of this adhesion family, suggesting that this new family of proteins may be encoded by a cluster of "adhesion protein" loci.

Authors
Tedder, TF; Isaacs, CM; Ernst, TJ; Demetri, GD; Adler, DA; Disteche, CM
MLA Citation
Tedder, TF, Isaacs, CM, Ernst, TJ, Demetri, GD, Adler, DA, and Disteche, CM. "Isolation and chromosomal localization of cDNAs encoding a novel human lymphocyte cell surface molecule, LAM-1. Homology with the mouse lymphocyte homing receptor and other human adhesion proteins." J Exp Med 170.1 (July 1, 1989): 123-133.
PMID
2473156
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
170
Issue
1
Publish Date
1989
Start Page
123
End Page
133

Structure of the gene encoding the human B lymphocyte differentiation antigen CD20 (B1).

The CD20 (B1) molecule is a differentiation Ag found only on the surface of B lymphocytes. This structurally unique phosphoprotein plays a role in the regulation of human B cell proliferation and differentiation. In this report genomic DNA clones containing the human CD20 gene were isolated and the structure of the CD20 gene determined. Southern blot analysis revealed that CD20 mRNA was transcribed from a single-copy gene. The CD20 gene was 16 kb long and was composed of eight exons. The first exon marked the major transcription initiation site as determined by primer extension and S1 nuclease analysis. The translation initiation codon was located within the third exon. Exon VIII encoded the COOH terminus of the CD20 protein and the long 3' untranslated region. Three forms of CD20 mRNA were identified that all encode an identical protein product. The dominant form of 2.8 kb results from usage of exons I through VIII, whereas a second form that is 263 bp shorter had exon I spliced into an internal 3' splice site within exon III thereby skipping exon II. A minor 3.4-kb mRNA species most likely results from an uncharacterized upstream exon(s) splicing into an internal 3' slice site located in exon I. Nucleotide sequences of cDNA clones representative of each of these RNA forms are presented. The 5' splice site following exon V was found to be divergent from the consensus splice sequence. A relationship between the individual peptides encoded by the six exons and structurally distinct regions of the CD20 protein is likely.

Authors
Tedder, TF; Klejman, G; Schlossman, SF; Saito, H
MLA Citation
Tedder, TF, Klejman, G, Schlossman, SF, and Saito, H. "Structure of the gene encoding the human B lymphocyte differentiation antigen CD20 (B1)." J Immunol 142.7 (April 1, 1989): 2560-2568.
PMID
2466899
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
142
Issue
7
Publish Date
1989
Start Page
2560
End Page
2568

The gene that encodes the human CD20 (B1) differentiation antigen is located on chromosome 11 near the t(11;14)(q13;q32) translocation site.

The human CD20 gene (B1) encodes a B lymphocyte-specific, cell-surface molecule that is involved in B cell activation and differentiation. We report that the CD20 gene is located on human chromosome 11 at position q12-q13. The location of CD20 was determined by in situ hybridization and was further confirmed by Southern blot analysis of DNA from rodent/human hybrids that contained only portions of human chromosome 11. This localization places the CD20 gene near the site of the t(11;14)(q13;q32) translocation that is found in a subgroup of B cell-lineage malignancies. The site of this translocation has been previously identified by DNA cloning and termed bcl-1. The CD20 gene was found to lie on the centromeric side of bcl-1 on chromosome 11 and to be separated from bcl-1 by at least 50 kb of DNA. These results raise the possibility that alterations in the expression of the CD20 gene may result after the t(11;14) chromosomal alteration.

Authors
Tedder, TF; Disteche, CM; Louie, E; Adler, DA; Croce, CM; Schlossman, SF; Saito, H
MLA Citation
Tedder, TF, Disteche, CM, Louie, E, Adler, DA, Croce, CM, Schlossman, SF, and Saito, H. "The gene that encodes the human CD20 (B1) differentiation antigen is located on chromosome 11 near the t(11;14)(q13;q32) translocation site." J Immunol 142.7 (April 1, 1989): 2555-2559.
PMID
2466898
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
142
Issue
7
Publish Date
1989
Start Page
2555
End Page
2559

Amplification of suppressor inducer pathway with monoclonal antibody, anti-2H4, identifying a novel epitope of the common leukocyte antigen/T200 antigen.

The 2H4 antigen, comprised of a 200/220-kDa glycoprotein of the leukocyte common antigen (LCA) family, is expressed on a suppressor inducer, but not a helper inducer subset of T4 cells. Earlier studies have demonstrated that the T4+2H4+ subset of cells maximally responded to the AMLR and this molecule has an important role in generated suppressor signals in AMLR/Con A-activated T cell systems. In the present study, we examined the effect of a series of monoclonal antibodies including anti-2H4 antibody on the initial activation of T4 cells in response to self-Ia antigens. We found that the addition of anti-2H4 antibody resulted in an augmentation of the proliferative response of T4 cells in AMLR, whereas other antibodies reactive with LCA/T200 antigens lacked this ability. Furthermore, anti-2H4 antibody enhanced both IL-2 production and IL-2R expression in this AMLR system. This enhancing effect was inhibited by anti-T3 antibody. Moreover, the suppressor inducer function of AMLR T4 cells was enhanced with anti-2H4 antibody by increasing the number of 2H4+ cells with high antigen density. Taken together, these results suggest that the 2H4 antigen may serve as an accessory structure for enhancing the activation of the T4+2H4+ suppressor inducer subset at initiation of cell triggering.

Authors
Takeuchi, T; Rudd, CE; Tedder, TF; Schlossman, SF; Morimoto, C
MLA Citation
Takeuchi, T, Rudd, CE, Tedder, TF, Schlossman, SF, and Morimoto, C. "Amplification of suppressor inducer pathway with monoclonal antibody, anti-2H4, identifying a novel epitope of the common leukocyte antigen/T200 antigen." Cell Immunol 118.1 (January 1989): 68-84.
PMID
2463098
Source
pubmed
Published In
Cellular Immunology
Volume
118
Issue
1
Publish Date
1989
Start Page
68
End Page
84

Cloning of a complementary DNA encoding a new mouse B lymphocyte differentiation antigen, homologous to the human B1 (CD20) antigen, and localization of the gene to chromosome 19.