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Yi, John S

Overview:

I am an immunologist, with a focus to characterize the immune system in response to infectious and non-infectious diseases including cancer, HIV, autoimmune disease, and transplantation. My goals are to identify novel biomarkers/immune signatures that clinicians can utilize to diagnosis, predict disease outcomes, and determine patients' response to treatment. 

Positions:

Assistant Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2010

Ph.D. — University of Alabama at Birmingham

Grants:

Magnetically directed single cell transcriptome analysis in HIV latency

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 2014
End Date
August 31, 2021

Role of CD4 T cell subsets as drivers of MG disease

Administered By
Duke Clinical Research Institute
AwardedBy
Myasthenia Gravis Foundation
Role
Co Investigator
Start Date
January 01, 2016
End Date
December 31, 2018

The interface of B and T cells in Transplant

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
Cystic Fibrosis Foundation Therapeutics, Inc.
Role
Research Associate
Start Date
December 01, 2016
End Date
November 30, 2018

Acetylcholine receptor binding B cells as biomarker for myasthenia gravis

Administered By
Neurology, Neuromuscular Disease
AwardedBy
AFM-Telethon
Role
Co Investigator
Start Date
April 27, 2017
End Date
April 26, 2018

VTEU Task D Option 2 Protocol FY.2015.A4D14.0033

Administered By
Duke Human Vaccine Institute
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 01, 2015
End Date
February 28, 2018

VTEU Task D Option 3 Protocol FY.2015.A4D14.0033

Administered By
Duke Human Vaccine Institute
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 01, 2015
End Date
February 28, 2018

VTEU Task D Option 4 Protocol FY.2015.A4D14.0033

Administered By
Duke Human Vaccine Institute
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 01, 2015
End Date
February 28, 2018

High Impact Pilot Project on Myasthenia Gravis and Related Neuromuscular Junction Disorders

Administered By
Neurology, Neuromuscular Disease
AwardedBy
Myasthenia Gravis Foundation
Role
Co Investigator
Start Date
July 01, 2014
End Date
June 30, 2017

Profiling of ACHR-Specific B Cells in Myasthenia Gravis

Administered By
Surgery, Surgical Sciences
AwardedBy
Myasthenia Gravis Foundation of Illinois
Role
Principal Investigator
Start Date
July 01, 2015
End Date
December 31, 2016

VTEU Task A Protocol FY.2015.A4D14.0033

Administered By
Duke Human Vaccine Institute
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 01, 2015
End Date
August 31, 2016
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Publications:

Dendritic cells enhance polyfunctionality of adoptively transferred T cells which target cytomegalovirus in glioblastoma.

Median survival for glioblastoma (GBM) remains <15 months. Human Cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DC would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here we report prospective results of a pilot trial in which 22 patients with newly-diagnosed GBM were initially enrolled of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-Saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.

Authors
Reap, E; Suryadevara, CM; Batich, KA; Sanchez-Perez, L; Archer, GE; Schmittling, RJ; Norberg, PK; Herndon, JE; Healy, P; Congdon, KL; Gedeon, PC; Campbell, OC; Swartz, AM; Riccione, KA; Yi, JS; Hossain-Ibrahim, MK; Saraswathula, A; Nair, SK; Dunn-Pirio, AM; Broome, TM; Weinhold, KJ; Desjardins, A; Vlahovic, G; Mclendon, R; Friedman, AH; Friedman, HS; Bigner, DD; Fecci, PE; Mitchell, DA; Sampson, JH
MLA Citation
Reap, E, Suryadevara, CM, Batich, KA, Sanchez-Perez, L, Archer, GE, Schmittling, RJ, Norberg, PK, Herndon, JE, Healy, P, Congdon, KL, Gedeon, PC, Campbell, OC, Swartz, AM, Riccione, KA, Yi, JS, Hossain-Ibrahim, MK, Saraswathula, A, Nair, SK, Dunn-Pirio, AM, Broome, TM, Weinhold, KJ, Desjardins, A, Vlahovic, G, Mclendon, R, Friedman, AH, Friedman, HS, Bigner, DD, Fecci, PE, Mitchell, DA, and Sampson, JH. "Dendritic cells enhance polyfunctionality of adoptively transferred T cells which target cytomegalovirus in glioblastoma." Cancer research (November 2017).
PMID
29093005
Source
epmc
Published In
Cancer Research
Publish Date
2017
DOI
10.1158/0008-5472.can-17-0469

Immune Activation in Early Stage Non-Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab.

To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early stage non-small cell lung cancer (NSCLC) patients.This is a single-arm chemotherapy plus phased ipilimumab Phase II study of 24 treatment-naïve patients with Stage IB-IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles.Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28 dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4+ cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8+ cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated TILs than those observed in PBMCs. Surprisingly, we found 4 cases of pre-existing tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating Tregs and MDSCs.This study did not meet the primary endpoint of detecting an increase in blood based tumor associated antigen T cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunological data from combined immune checkpoint blockade immunotherapies.

Authors
Yi, JS; Ready, N; Healy, P; Dumbauld, C; Osborne, R; Berry, M; Shoemaker, D; Clarke, J; Crawford, J; Tong, BC; Harpole, D; D'Amico, TA; McSherry, F; Dunphy, F; McCall, SJ; Christensen, JD; Wang, X; Weinhold, KJ
MLA Citation
Yi, JS, Ready, N, Healy, P, Dumbauld, C, Osborne, R, Berry, M, Shoemaker, D, Clarke, J, Crawford, J, Tong, BC, Harpole, D, D'Amico, TA, McSherry, F, Dunphy, F, McCall, SJ, Christensen, JD, Wang, X, and Weinhold, KJ. "Immune Activation in Early Stage Non-Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab." Clinical cancer research : an official journal of the American Association for Cancer Research (September 26, 2017).
PMID
28951518
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Publish Date
2017
DOI
10.1158/1078-0432.ccr-17-2005

B cells in the pathophysiology of myasthenia gravis.

Myasthenia gravis (MG) is an archetypal autoimmune disease. The pathology is characterized by autoantibodies to the acetylcholine receptor (AChR) in most patients or to muscle-specific tyrosine kinase (MuSK) in others and to a growing number of other postsynaptic proteins in smaller subsets. A decrease in the number of functional AChRs or functional interruption of the AChR within the muscle end plate of the neuromuscular junction is caused by pathogenic autoantibodies. Although the molecular immunology underpinning the pathology is well understood, much remains to be learned about the cellular immunology contributing to the production of autoantibodies. This Review documents research concerning the immunopathology of MG, bringing together evidence principally from human studies with an emphasis on the role of adaptive immunity and B cells in particular. Proposed mechanisms for autoimmunity, which take into account that different types of MG may incorporate divergent immunopathology, are offered. Muscle Nerve, 2017.

Authors
Yi, JS; Guptill, JT; Stathopoulos, P; Nowak, RJ; O'Connor, KC
MLA Citation
Yi, JS, Guptill, JT, Stathopoulos, P, Nowak, RJ, and O'Connor, KC. "B cells in the pathophysiology of myasthenia gravis." Muscle & nerve (September 20, 2017).
PMID
28940642
Source
epmc
Published In
Muscle and Nerve
Publish Date
2017
DOI
10.1002/mus.25973

B10 Cell Frequencies and Suppressive Capacity in Myasthenia Gravis Are Associated with Disease Severity.

Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated disease. The mechanisms for loss of self-tolerance in this disease are not well understood, and recently described regulatory B cell (Breg) subsets have not been thoroughly investigated. B10 cells are a subset of Bregs identified by the production of the immunosuppressive cytokine, interleukin-10 (IL-10). B10 cells are known to strongly inhibit B- and T-cell inflammatory responses in animal models and are implicated in human autoimmunity. In this study, we examined quantitative and qualitative aspects of B10 cells in acetylcholine receptor autoantibody positive MG (AChR-MG) patients and healthy controls. We observed reduced B10 cell frequencies in AChR-MG patients, which inversely correlated with disease severity. Disease severity also affected the function of B10 cells, as B10 cells in the moderate/severe group of MG patients were less effective in suppressing CD4 T-cell proliferation. These results suggest that B10 cell frequencies may be a useful biomarker of disease severity, and therapeutics designed to restore B10 cell frequencies could hold promise as a treatment for this disease through restoration of self-tolerance.

Authors
Yi, JS; Russo, MA; Massey, JM; Juel, V; Hobson-Webb, LD; Gable, K; Raja, SM; Balderson, K; Weinhold, KJ; Guptill, JT
MLA Citation
Yi, JS, Russo, MA, Massey, JM, Juel, V, Hobson-Webb, LD, Gable, K, Raja, SM, Balderson, K, Weinhold, KJ, and Guptill, JT. "B10 Cell Frequencies and Suppressive Capacity in Myasthenia Gravis Are Associated with Disease Severity." Frontiers in neurology 8 (January 2017): 34-.
Website
http://hdl.handle.net/10161/15573
PMID
28239367
Source
epmc
Published In
Frontiers in Neurology
Volume
8
Publish Date
2017
Start Page
34
DOI
10.3389/fneur.2017.00034

Effect of therapeutic plasma exchange on immunoglobulins in myasthenia gravis.

An integrated understanding of therapeutic plasma exchange (TPE) effects on immunoglobulins, autoantibodies, and natural or acquired (vaccine) protective antibodies in patients with autoimmune myasthenia gravis (MG) is lacking. Prior studies measured TPE effects in healthy volunteers or heterogeneous autoimmune disease populations. We prospectively profiled plasma IgA, IgM, IgG, IgG subclasses (IgG1-4), acetylcholine receptor autoantibodies (AChR+), and protective antibodies in patients with AChR + MG receiving TPE for an exacerbation. TPE was performed according to institutional practice and patients were profiled for up to 12 weeks. Ten patients were enrolled (median age = 72.9 years; baseline MG-Composite = 21; median TPE treatments = 6 during their first course) and all improved. The maximum decrease in all immunoglobulins, including AChR autoantibodies, was achieved on the final day of the first TPE course (∼60-70% reduction). Three weeks post-TPE, mean AChR autoantibody, total IgG, IgG1, and IgG2 titers were below the reference range and had not recovered within 20% of baseline, whereas other measured immunoglobulins approached baseline values. We did not generally observe an "overshoot" of immunoglobulins above pre-TPE levels or accelerated recovery of pathologic AChR autoantibodies. Protective antibody profiles showed similar patterns as other IgGs and were detectable at levels associated with protection from infection. A slow return to baseline for IgGs (except IgG3) was observed, and we did not observe any obvious effect of concomitant medications on this recovery. Collectively, these findings enhance our understanding of the immunological effects of TPE and further support the concept of rapid immunoglobulin depletion for the treatment of patients with MG.

Authors
Guptill, JT; Juel, VC; Massey, JM; Anderson, AC; Chopra, M; Yi, JS; Esfandiari, E; Buchanan, T; Smith, B; Atherfold, P; Jones, E; Howard, JF
MLA Citation
Guptill, JT, Juel, VC, Massey, JM, Anderson, AC, Chopra, M, Yi, JS, Esfandiari, E, Buchanan, T, Smith, B, Atherfold, P, Jones, E, and Howard, JF. "Effect of therapeutic plasma exchange on immunoglobulins in myasthenia gravis." Autoimmunity 49.7 (November 2016): 472-479.
PMID
27684107
Source
epmc
Published In
Autoimmunity (Informa)
Volume
49
Issue
7
Publish Date
2016
Start Page
472
End Page
479
DOI
10.1080/08916934.2016.1214823

Adaptive immune response to therapy in hmgcr autoantibody myopathy.

We evaluated the response to immunosuppression in a case of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)-autoantibody myopathy.T- and B-cell subsets were determined by flow cytometry pre- and posttherapy.Baseline immune profiling demonstrated strikingly elevated T-follicular helper (Tfh) cells and plasmablasts. Immunosuppression resulted in clinical improvement and decreased Tfh cells, plasmablasts, and autoantibodies.Immune profiling in HMGCR-autoantibody myopathy suggests a B-cell-mediated disease. Tfh cells and plasmablasts may be therapeutic biomarkers.

Authors
Yi, JS; Russo, MA; Weinhold, KJ; Guptill, JT
MLA Citation
Yi, JS, Russo, MA, Weinhold, KJ, and Guptill, JT. "Adaptive immune response to therapy in hmgcr autoantibody myopathy." Muscle & nerve 53.2 (February 2016): 313-317.
PMID
26492512
Source
epmc
Published In
Muscle and Nerve
Volume
53
Issue
2
Publish Date
2016
Start Page
313
End Page
317
DOI
10.1002/mus.24947

Characterizing the Switching Thresholds of Magnetophoretic Transistors.

The switching thresholds of magnetophoretic transistors for sorting cells in microfluidic environments are characterized. The transistor operating conditions require short 20-30 mA pulses of electrical current. By demonstrating both attractive and repulsive transistor modes, a single transistor architecture is used to implement the full write cycle for importing and exporting single cells in specified array sites.

Authors
Abedini-Nassab, R; Joh, DY; Van Heest, MA; Yi, JS; Baker, C; Taherifard, Z; Margolis, DM; Garcia, JV; Chilkoti, A; Murdoch, DM; Yellen, BB
MLA Citation
Abedini-Nassab, R, Joh, DY, Van Heest, MA, Yi, JS, Baker, C, Taherifard, Z, Margolis, DM, Garcia, JV, Chilkoti, A, Murdoch, DM, and Yellen, BB. "Characterizing the Switching Thresholds of Magnetophoretic Transistors." Advanced materials (Deerfield Beach, Fla.) 27.40 (October 2015): 6176-6180.
Website
http://hdl.handle.net/10161/10827
PMID
26349853
Source
epmc
Published In
Advanced Materials
Volume
27
Issue
40
Publish Date
2015
Start Page
6176
End Page
6180
DOI
10.1002/adma.201502352

EFFECT OF THERAPEUTIC PLASMA EXCHANGE ON IMMUNOGLOBULINS

Authors
Guptill, JT; Juel, VC; Massey, JM; Anderson, AC; Yi, JS; Chopra, M; Jr, HJF
MLA Citation
Guptill, JT, Juel, VC, Massey, JM, Anderson, AC, Yi, JS, Chopra, M, and Jr, HJF. "EFFECT OF THERAPEUTIC PLASMA EXCHANGE ON IMMUNOGLOBULINS." October 2015.
Source
wos-lite
Published In
Muscle and Nerve
Volume
52
Publish Date
2015
Start Page
S140
End Page
S140

T CELL REACTIVITY IN INCLUSION BODY MYOSITIS (IBM)

Authors
Hobson-Webb, LD; Guptill, JT; Russo, MA; Anderson, AC; Massey, JM; Gable, K; Juel, VC; Massey, EW; Sanders, DB; Yi, JS
MLA Citation
Hobson-Webb, LD, Guptill, JT, Russo, MA, Anderson, AC, Massey, JM, Gable, K, Juel, VC, Massey, EW, Sanders, DB, and Yi, JS. "T CELL REACTIVITY IN INCLUSION BODY MYOSITIS (IBM)." September 2015.
Website
http://hdl.handle.net/10161/10828
Source
wos-lite
Published In
Muscle and Nerve
Volume
52
Publish Date
2015
Start Page
S11
End Page
S11

Characterization of B cells in muscle-specific kinase antibody myasthenia gravis.

To characterize B-cell subsets in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG).In accordance with Human Immunology Project Consortium guidelines, we performed polychromatic flow cytometry and ELISA assays in peripheral blood samples from 18 patients with MuSK MG and 9 healthy controls. To complement a B-cell phenotype assay that evaluated maturational subsets, we measured B10 cell percentages, plasma B cell-activating factor (BAFF) levels, and MuSK antibody titers. Immunologic variables were compared with healthy controls and clinical outcome measures.As expected, patients treated with rituximab had high percentages of transitional B cells and plasmablasts and thus were excluded from subsequent analysis. The remaining patients with MuSK MG and controls had similar percentages of total B cells and naïve, memory, isotype-switched, plasmablast, and transitional B-cell subsets. However, patients with MuSK MG had higher BAFF levels and lower percentages of B10 cells. In addition, we observed an increase in MuSK antibody levels with more severe disease.We found prominent B-cell pathology in the distinct form of MG with MuSK autoantibodies. Increased BAFF levels have been described in other autoimmune diseases, including acetylcholine receptor antibody-positive MG. This finding suggests a role for BAFF in the survival of B cells in MuSK MG, which has important therapeutic implications. B10 cells, a recently described rare regulatory B-cell subset that potently blocks Th1 and Th17 responses, were reduced, which suggests a potential mechanism for the breakdown in immune tolerance in patients with MuSK MG.

Authors
Guptill, JT; Yi, JS; Sanders, DB; Guidon, AC; Juel, VC; Massey, JM; Howard, JF; Scuderi, F; Bartoccioni, E; Evoli, A; Weinhold, KJ
MLA Citation
Guptill, JT, Yi, JS, Sanders, DB, Guidon, AC, Juel, VC, Massey, JM, Howard, JF, Scuderi, F, Bartoccioni, E, Evoli, A, and Weinhold, KJ. "Characterization of B cells in muscle-specific kinase antibody myasthenia gravis." Neurology(R) neuroimmunology & neuroinflammation 2.2 (April 2015): e77-.
Website
http://hdl.handle.net/10161/10206
PMID
25745635
Source
epmc
Published In
Neurology: Neuroimmunology and Neuroinflammation
Volume
2
Issue
2
Publish Date
2015
Start Page
e77
DOI
10.1212/nxi.0000000000000077

COMPARISON OF B10 CELLS IN IMMUNOSLTPPRESSED AND IMMUNOSUPPRESSION NAIVE ACHR plus MG

Authors
Yi, JS; Sanders, DB; Massey, JM; Juel, VC; Weinhold, KJ; Guptill, JT
MLA Citation
Yi, JS, Sanders, DB, Massey, JM, Juel, VC, Weinhold, KJ, and Guptill, JT. "COMPARISON OF B10 CELLS IN IMMUNOSLTPPRESSED AND IMMUNOSUPPRESSION NAIVE ACHR plus MG." October 2014.
Source
wos-lite
Published In
Muscle and Nerve
Volume
50
Issue
4
Publish Date
2014
Start Page
716
End Page
716

Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis.

Muscle specific tyrosine kinase myasthenia gravis (MuSK MG) is a form of autoimmune MG that predominantly affects women and has unique clinical features, including prominent bulbar weakness, muscle atrophy, and excellent response to therapeutic plasma exchange. Patients with MuSK MG have predominantly IgG4 autoantibodies directed against MuSK on the postsynaptic muscle membrane. Lymphocyte functionality has not been reported in this condition. The goal of this study was to characterize T cell responses in patients with MuSK MG. Intracellular production of IFN-gamma, TNF-alpha, IL-2, IL-17, and IL-21 by CD4+ and CD8+ T cells was measured by polychromatic flow cytometry in peripheral blood samples from 11 Musk MG patients and 10 healthy controls. Only one MuSK MG patient was not receiving immunosuppressive therapy. Regulatory T cells (Treg) were also included in our analysis to determine if changes in T cell function were due to altered Treg frequencies. CD8+ T cells from MuSK MG patients had higher frequencies of polyfunctional responses than controls, and CD4+ T cells had higher IL-2, TNF-alpha, and IL-17. MuSK MG patients had a higher percentage of CD4+ T cells producing combinations of IFN-gamma/IL-2/TNF-gamma, TNF-alpha/IL-2, and IFN-gamma/TNF-alpha. Interestingly, Treg numbers and CD39 expression were not different from control values. MuSK MG patients had increased frequencies of Th1 and Th17 cytokines and were primed for polyfunctional proinflammatory responses that cannot be explained by a defect in CD39 expression or Treg number.

Authors
Yi, JS; Guidon, A; Sparks, S; Osborne, R; Juel, VC; Massey, JM; Sanders, DB; Weinhold, KJ; Guptill, JT
MLA Citation
Yi, JS, Guidon, A, Sparks, S, Osborne, R, Juel, VC, Massey, JM, Sanders, DB, Weinhold, KJ, and Guptill, JT. "Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis." J Autoimmun 52 (August 2014): 130-138.
Website
http://hdl.handle.net/10161/10224
PMID
24378287
Source
pubmed
Published In
Journal of Autoimmunity
Volume
52
Publish Date
2014
Start Page
130
End Page
138
DOI
10.1016/j.jaut.2013.12.005

Prolonged B-cell depletion in MuSK myasthenia gravis following rituximab treatment.

Authors
Yi, JS; Decroos, EC; Sanders, DB; Weinhold, KJ; Guptill, JT
MLA Citation
Yi, JS, Decroos, EC, Sanders, DB, Weinhold, KJ, and Guptill, JT. "Prolonged B-cell depletion in MuSK myasthenia gravis following rituximab treatment." Muscle Nerve 48.6 (December 2013): 992-993. (Letter)
Website
http://hdl.handle.net/10161/10207
PMID
24006142
Source
pubmed
Published In
Muscle and Nerve
Volume
48
Issue
6
Publish Date
2013
Start Page
992
End Page
993
DOI
10.1002/mus.24063

Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections.

During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon (IFN)-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce IFN-γ and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. The unresponsiveness of exhausted CD8 T cells is associated with downregulation of the IL-18-receptor-α (IL-18Rα). Although IL-18Rα expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18Rα(lo) exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18Rα downregulation, we tracked the fate of IL-18Rα-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18Rα affects the initial but not later phases of the response. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18Rα(hi) memory cells upregulated CD25 and produced IFN-γ, the IL-18Rα(lo) exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial co-infections.

Authors
Ingram, JT; Yi, JS; Zajac, AJ
MLA Citation
Ingram, JT, Yi, JS, and Zajac, AJ. "Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections." PLoS pathogens 7.9 (September 29, 2011): e1002273-.
Website
http://hdl.handle.net/10161/10220
PMID
21980291
Source
epmc
Published In
PLoS pathogens
Volume
7
Issue
9
Publish Date
2011
Start Page
e1002273
DOI
10.1371/journal.ppat.1002273

Interleukin-21: a multifunctional regulator of immunity to infections.

Interleukin-21 (IL-21) is a cytokine that has broad effects on both innate and adaptive immune responses. The roles of IL-21 in determining immunity to infections are currently being defined, and notably, it has been shown that IL-21 is most critical for sustaining T cell responses during chronic viral infections. This article discusses our current understanding of the immunobiology of IL-21, as well as its known and potential roles in influencing immunity to infections.

Authors
Yi, JS; Cox, MA; Zajac, AJ
MLA Citation
Yi, JS, Cox, MA, and Zajac, AJ. "Interleukin-21: a multifunctional regulator of immunity to infections." Microbes and infection 12.14-15 (December 2010): 1111-1119. (Review)
Website
http://hdl.handle.net/10161/10223
PMID
20817119
Source
epmc
Published In
Microbes and Infection
Volume
12
Issue
14-15
Publish Date
2010
Start Page
1111
End Page
1119
DOI
10.1016/j.micinf.2010.08.008

IL-21 deficiency influences CD8 T cell quality and recall responses following an acute viral infection.

CD4 T cells are principal producers of IL-21 and are often required for optimal CD8 T cell responses. Therefore, we investigated the importance of IL-21 in determining the phenotypic attributes, functional quality, and maintenance of antiviral CD8 T cells following acute infection with the prototypic mouse pathogen lymphocytic choriomeningitis virus. Previous reports have documented an obligatory role for IL-21 in sustaining CD8 T cell responses during chronic infections. Here we show that the requirements for IL-21 are less stringent following acute infections; however, in the absence of IL-21, the capacity of CD8 T cells to attain the polyfunctional trait of IL-2 production is consistently reduced during both the effector and memory phases. This is further supported by in vitro studies showing that the addition of IL-21 promotes the differentiation of IL-2-producing CD8 T cells. Although the generation of memory CD8 T cells, which are capable of mounting protective recall responses, proceeds independently of IL-21, we demonstrate that IL-21 does function to support secondary responses, especially under competitive conditions. Collectively, these studies highlight the potential roles of IL-21 in determining the quality of CD8 T cell responses postinfection.

Authors
Yi, JS; Ingram, JT; Zajac, AJ
MLA Citation
Yi, JS, Ingram, JT, and Zajac, AJ. "IL-21 deficiency influences CD8 T cell quality and recall responses following an acute viral infection." Journal of immunology (Baltimore, Md. : 1950) 185.8 (October 2010): 4835-4845.
Website
http://hdl.handle.net/10161/10225
PMID
20844201
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
185
Issue
8
Publish Date
2010
Start Page
4835
End Page
4845
DOI
10.4049/jimmunol.1001032

T-cell exhaustion: characteristics, causes and conversion.

T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state.

Authors
Yi, JS; Cox, MA; Zajac, AJ
MLA Citation
Yi, JS, Cox, MA, and Zajac, AJ. "T-cell exhaustion: characteristics, causes and conversion." Immunology 129.4 (April 2010): 474-481. (Review)
Website
http://hdl.handle.net/10161/10222
PMID
20201977
Source
epmc
Published In
Immunology
Volume
129
Issue
4
Publish Date
2010
Start Page
474
End Page
481
DOI
10.1111/j.1365-2567.2010.03255.x

A vital role for interleukin-21 in the control of a chronic viral infection.

Understanding the factors that regulate the induction, quality, and longevity of antiviral T cell responses is essential for devising rational strategies to prevent or combat infections. In this study, we show that interleukin-21 (IL-21), likely produced by CD4+ T cells, directly influences the generation of polyfunctional CD8+ T cells and that the number of CD4+ T cells that produce IL-21 differs markedly between acute and chronic infections. IL-21 regulates the development of CD8+ T cell exhaustion and the ability to contain chronic lymphocytic choriomeningitis virus infection. Thus, IL-21 serves as a critical helper factor that shapes the functional quality of antiviral CD8+ T cells and is required for viral control.

Authors
Yi, JS; Du, M; Zajac, AJ
MLA Citation
Yi, JS, Du, M, and Zajac, AJ. "A vital role for interleukin-21 in the control of a chronic viral infection." Science (New York, N.Y.) 324.5934 (June 2009): 1572-1576.
Website
http://hdl.handle.net/10161/10208
PMID
19443735
Source
epmc
Published In
Science
Volume
324
Issue
5934
Publish Date
2009
Start Page
1572
End Page
1576
DOI
10.1126/science.1175194

Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice.

Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4+ T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

Authors
Hsu, H-C; Yang, P; Wang, J; Wu, Q; Myers, R; Chen, J; Yi, J; Guentert, T; Tousson, A; Stanus, AL; Le, T-VL; Lorenz, RG; Xu, H; Kolls, JK; Carter, RH; Chaplin, DD; Williams, RW; Mountz, JD
MLA Citation
Hsu, H-C, Yang, P, Wang, J, Wu, Q, Myers, R, Chen, J, Yi, J, Guentert, T, Tousson, A, Stanus, AL, Le, T-VL, Lorenz, RG, Xu, H, Kolls, JK, Carter, RH, Chaplin, DD, Williams, RW, and Mountz, JD. "Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice." Nature immunology 9.2 (February 2008): 166-175.
Website
http://hdl.handle.net/10161/10221
PMID
18157131
Source
epmc
Published In
Nature Immunology
Volume
9
Issue
2
Publish Date
2008
Start Page
166
End Page
175
DOI
10.1038/ni1552

The requirement of reversible cysteine sulfenic acid formation for T cell activation and function.

Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in mediating cellular responses. We have examined the importance of reversible cysteine sulfenic acid formation in naive CD8(+) T cell activation and proliferation. We observed that, within minutes of T cell activation, naive CD8(+) T cells increased ROI levels in a manner dependent upon Ag concentration. Increased ROI resulted in elevated levels of cysteine sulfenic acid in the total proteome. Analysis of specific proteins revealed that the protein tyrosine phosphatases SHP-1 and SHP-2, as well as actin, underwent increased sulfenic acid modification following stimulation. To examine the contribution of reversible cysteine sulfenic acid formation to T cell activation, increasing concentrations of 5,5-dimethyl-1,3-cyclohexanedione (dimedone), which covalently binds to cysteine sulfenic acid, were added to cultures. Subsequent experiments demonstrated that the reversible formation of cysteine sulfenic acid was critical for ERK1/2 phosphorylation, calcium flux, cell growth, and proliferation of naive CD8(+) and CD4(+) T cells. We also found that TNF-alpha production by effector and memory CD8(+) T cells was more sensitive to the inhibition of reversible cysteine sulfenic acid formation than IFN-gamma. Together, these results demonstrate that reversible cysteine sulfenic acid formation is an important regulatory mechanism by which CD8(+) T cells are able to modulate signaling, proliferation, and function.

Authors
Michalek, RD; Nelson, KJ; Holbrook, BC; Yi, JS; Stridiron, D; Daniel, LW; Fetrow, JS; King, SB; Poole, LB; Grayson, JM
MLA Citation
Michalek, RD, Nelson, KJ, Holbrook, BC, Yi, JS, Stridiron, D, Daniel, LW, Fetrow, JS, King, SB, Poole, LB, and Grayson, JM. "The requirement of reversible cysteine sulfenic acid formation for T cell activation and function." Journal of immunology (Baltimore, Md. : 1950) 179.10 (November 2007): 6456-6467.
PMID
17982034
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
179
Issue
10
Publish Date
2007
Start Page
6456
End Page
6467
DOI
10.4049/jimmunol.179.10.6456

Electron transport complex I is required for CD8+ T cell function.

After Ag encounter, CD8+ T cells become activated and begin to proliferate. Early during infection, when Ag-specific effector CD8+ T cells are proliferating, producing cytokines, and lysing infected cells in vivo, their mitochondrial potential is increased. The purpose of the experiments presented here was to determine whether mitochondrial function was required for CD8+ T cell function. To block mitochondrial function, transgenic CD8+ T cells were incubated with increasing doses of rotenone, an inhibitor of electron transport complex I. Within minutes of T cell activation, rotenone incubation decreased the production of H(2)O(2), calcium flux, and ERK1/2 phosphorylation. Failure to undergo signal transduction resulted in a decrease in T cell division initiated by peptide-coated cells, CD3/CD28 Abs, and PMA/ionomycin stimulation. Decreased function following rotenone incubation was not restricted to naive cells, as effector and memory CD8+ T cells isolated directly ex vivo from lymphocytic choriomeningitis virus-infected mice displayed decreased production of IFN-gamma and TNF-alpha production after peptide stimulation. Furthermore, incubation with rotenone decreased degranulation of effector and memory cells, a critical step in the cytolysis of infected cells. These data suggest that electron transport complex I is required for CD8+ T cell signal transduction, proliferation, cytokine production, and degranulation.

Authors
Yi, JS; Holbrook, BC; Michalek, RD; Laniewski, NG; Grayson, JM
MLA Citation
Yi, JS, Holbrook, BC, Michalek, RD, Laniewski, NG, and Grayson, JM. "Electron transport complex I is required for CD8+ T cell function." Journal of immunology (Baltimore, Md. : 1950) 177.2 (July 2006): 852-862.
PMID
16818739
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
177
Issue
2
Publish Date
2006
Start Page
852
End Page
862
DOI
10.4049/jimmunol.177.2.852

The Rise of Checkpoint Blockade Therapy to Front Line Cancer Therapy

Authors
Yi, JS
MLA Citation
Yi, JS. "The Rise of Checkpoint Blockade Therapy to Front Line Cancer Therapy." Ed. AH Lichtman. Translational Immunology Update.
Source
manual
Published In
Translational Immunology Update
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Research Areas:

  • Autoimmune Diseases
  • Biomarkers, Pharmacological
  • Cancer
  • Flow Cytometry
  • Immunologic Deficiency Syndromes
  • Immunology
  • Lungs--Transplantation
  • Neuromuscular Diseases