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Ciofani, Maria

Overview:


Transcriptional Regulation of Proinflammatory Lymphocytes

IL-17-expressing CD4 T helper (Th17) cells are important members of the intestinal immune cell community that contribute to protection against bacterial and fungal infections, and maintenance of intestinal homeostasis.  Although central to immunity, dysregulted Th17 cell function has been implicated in tissue inflammation and autoimmune disease (e.g. Inflammatory bowel disease, arthritis, and multiple sclerosis).  In order to understand this balance between healthy and pathogenic responses, we are interested in defining the transcriptional regulatory mechanisms that govern (1) Th17 cell specification from naive T cell precursors and, (2) Th17 cell effector plasticity during inflammation.  Combining genome-wide interrogation of regulatory information (transcription factor occupancy, chromatin accessibility, and transcriptional output) with gene-deficiency models in mice, we can dissect the contribution of key transcriptional regulators in proinflammatory T cell function.



We currently have open positions for students, postdoctoral fellows and a research technician.


Positions:

Assistant Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2007

Ph.D. — University of Toronto (Canada)

News:

Grants:

Regulatory Mechanisms of CD4+ T Cell Differentiation

Administered By
Biostatistics & Bioinformatics
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
August 21, 2017
End Date
June 30, 2021

The role of AP-1 family transcription factor networks in regulating Th17 cell effector identity

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2016
End Date
March 31, 2021

Basic Immunology Training Program

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

Transplant Infectious Diseases Interdisciplinary Research Training Grant

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Co-Director
Start Date
September 01, 2013
End Date
August 31, 2018

Network approach to dissecting genetic mediators of Multiple Sclerosis

Administered By
Immunology
AwardedBy
National Multiple Sclerosis Society
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2018
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Publications:

Cutting Edge: c-Maf Is Required for Regulatory T Cells To Adopt RORγt+ and Follicular Phenotypes.

Regulatory T cells (Tregs) adopt specialized phenotypes defined by coexpression of lineage-defining transcription factors, such as RORγt, Bcl-6, or PPARγ, alongside Foxp3. These Treg subsets have unique tissue distributions and diverse roles in maintaining organismal homeostasis. However, despite extensive functional characterization, the factors driving Treg specialization are largely unknown. In this article, we show that c-Maf is a critical transcription factor regulating this process in mice, essential for generation of both RORγt+ Tregs and T follicular regulatory cells, but not for adipose-resident Tregs. c-Maf appears to function primarily in Treg specialization, because IL-10 production, expression of other effector molecules, and general immune homeostasis are not c-Maf dependent. As in other T cells, c-Maf is induced in Tregs by IL-6 and TGF-β, suggesting that a combination of inflammatory and tolerogenic signals promote c-Maf expression. Therefore, c-Maf is a novel regulator of Treg specialization, which may integrate disparate signals to facilitate environmental adaptation.

Authors
Wheaton, JD; Yeh, C-H; Ciofani, M
MLA Citation
Wheaton, JD, Yeh, C-H, and Ciofani, M. "Cutting Edge: c-Maf Is Required for Regulatory T Cells To Adopt RORγt+ and Follicular Phenotypes." Journal of immunology (Baltimore, Md. : 1950) (November 10, 2017).
PMID
29127150
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Publish Date
2017
DOI
10.4049/jimmunol.1701134

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature Communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature Communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature Communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature Communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature Communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature Communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature Communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature Communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation.

T helper 17 (Th17) cell plasticity contributes to both immunity and autoimmunity; however, the factors that control lineage flexibility are mostly unknown. Here we show the activator protein-1 (AP-1) factor JunB is an essential regulator of Th17 cell identity. JunB activates expression of Th17 lineage-specifying genes and coordinately represses genes controlling Th1 and regulatory T-cell fate. JunB supports Th17 cell identity by regulating key AP-1 complex constituents. In particular, JunB limits the expression of the subset repressor IRF8, and impedes access of JunD to regulatory regions of alternative effector loci. Although dispensable for homeostatic Th17 cell development, JunB is required for induction and maintenance of Th17 effector responses in the inflammatory contexts of both acute infection and chronic autoimmunity in mice. Through regulatory network analysis, we show that JunB is a core regulator of global transcriptional programs that promote Th17 cell identity and restrict alternative CD4+ T-cell potential.AP-1 family transcription factors regulate CD4+ T helper cell differentiation. Here the authors show that the AP-1 member JunB is a nonredundant regulator of transcriptional programs that support Th17 cell identity and restrain alternative Th1 and Treg cell fates in inflammatory contexts of acute fungal infection and chronic autoimmunity.

Authors
Carr, TM; Wheaton, JD; Houtz, GM; Ciofani, M
MLA Citation
Carr, TM, Wheaton, JD, Houtz, GM, and Ciofani, M. "JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation." Nature communications 8.1 (August 21, 2017): 301-.
PMID
28824171
Source
epmc
Published In
Nature Communications
Volume
8
Issue
1
Publish Date
2017
Start Page
301
DOI
10.1038/s41467-017-00380-3

BATF Modulates the Th2 Locus Control Region and Regulates CD4+ T Cell Fate during Antihelminth Immunity.

The AP-1 factor basic leucine zipper transcription factor, ATF-like (BATF) is important for CD4+ Th17, Th9, and follicular Th cell development. However, its precise role in Th2 differentiation and function remains unclear, and the requirement for BATF in nonallergic settings of type-2 immunity has not been explored. In this article, we show that, in response to parasitic helminths, Batf-/- mice are unable to generate follicular Th and Th2 cells. As a consequence, they fail to establish productive type-2 immunity during primary and secondary infection. Batf-/- CD4+ T cells do not achieve type-2 cytokine competency, which implies that BATF plays a key role in the regulation of IL-4 and IL-13. In contrast to Th17 and Th9 cell subsets in which BATF binds directly to promoter and enhancer regions to regulate cytokine expression, our results show that BATF is significantly enriched at Rad50 hypersensitivity site (RHS)6 and RHS7 of the locus control region relative to AP-1 sites surrounding type-2 cytokine loci in Th2 cells. Indeed, Batf-/- CD4+ T cells do not obtain permissive epigenetic modifications within the Th2 locus, which were linked to RHS6 and RHS7 function. In sum, these findings reveal BATF as a central modulator of peripheral and humoral hallmarks of type-2 immunity and begin to elucidate a novel mechanism by which it regulates type-2 cytokine production through its modification of the Th2 locus control region.

Authors
Bao, K; Carr, T; Wu, J; Barclay, W; Jin, J; Ciofani, M; Reinhardt, RL
MLA Citation
Bao, K, Carr, T, Wu, J, Barclay, W, Jin, J, Ciofani, M, and Reinhardt, RL. "BATF Modulates the Th2 Locus Control Region and Regulates CD4+ T Cell Fate during Antihelminth Immunity." Journal of immunology (Baltimore, Md. : 1950) 197.11 (December 2016): 4371-4381.
PMID
27798167
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
197
Issue
11
Publish Date
2016
Start Page
4371
End Page
4381
DOI
10.4049/jimmunol.1601371

A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes.

Interferon regulatory factor 4 (IRF4) and IRF8 regulate B, T, macrophage, and dendritic cell differentiation. They are recruited to cis-regulatory Ets-IRF composite elements by PU.1 or Spi-B. How these IRFs target genes in most T cells is enigmatic given the absence of specific Ets partners. Chromatin immunoprecipitation sequencing in T helper 17 (T(H)17) cells reveals that IRF4 targets sequences enriched for activating protein 1 (AP-1)-IRF composite elements (AICEs) that are co-bound by BATF, an AP-1 factor required for T(H)17, B, and dendritic cell differentiation. IRF4 and BATF bind cooperatively to structurally divergent AICEs to promote gene activation and T(H)17 differentiation. The AICE motif directs assembly of IRF4 or IRF8 with BATF heterodimers and is also used in T(H)2, B, and dendritic cells. This genomic regulatory element and cognate factors appear to have evolved to integrate diverse immunomodulatory signals.

Authors
Glasmacher, E; Agrawal, S; Chang, AB; Murphy, TL; Zeng, W; Vander Lugt, B; Khan, AA; Ciofani, M; Spooner, CJ; Rutz, S; Hackney, J; Nurieva, R; Escalante, CR; Ouyang, W; Littman, DR; Murphy, KM; Singh, H
MLA Citation
Glasmacher, E, Agrawal, S, Chang, AB, Murphy, TL, Zeng, W, Vander Lugt, B, Khan, AA, Ciofani, M, Spooner, CJ, Rutz, S, Hackney, J, Nurieva, R, Escalante, CR, Ouyang, W, Littman, DR, Murphy, KM, and Singh, H. "A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes." Science 338.6109 (November 16, 2012): 975-980.
PMID
22983707
Source
pubmed
Published In
Science
Volume
338
Issue
6109
Publish Date
2012
Start Page
975
End Page
980
DOI
10.1126/science.1228309

A validated regulatory network for Th17 cell specification.

Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple data sets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease.

Authors
Ciofani, M; Madar, A; Galan, C; Sellars, M; Mace, K; Pauli, F; Agarwal, A; Huang, W; Parkhurst, CN; Muratet, M; Newberry, KM; Meadows, S; Greenfield, A; Yang, Y; Jain, P; Kirigin, FK; Birchmeier, C; Wagner, EF; Murphy, KM; Myers, RM; Bonneau, R; Littman, DR
MLA Citation
Ciofani, M, Madar, A, Galan, C, Sellars, M, Mace, K, Pauli, F, Agarwal, A, Huang, W, Parkhurst, CN, Muratet, M, Newberry, KM, Meadows, S, Greenfield, A, Yang, Y, Jain, P, Kirigin, FK, Birchmeier, C, Wagner, EF, Murphy, KM, Myers, RM, Bonneau, R, and Littman, DR. "A validated regulatory network for Th17 cell specification." Cell 151.2 (October 12, 2012): 289-303.
PMID
23021777
Source
pubmed
Published In
Cell
Volume
151
Issue
2
Publish Date
2012
Start Page
289
End Page
303
DOI
10.1016/j.cell.2012.09.016

Comparative and functional evaluation of in vitro generated to ex vivo CD8 T cells.

The generation of the cytotoxic CD8 T cell response is dependent on the functional outcomes imposed by the intrathymic constraints of differentiation and self-tolerance. Although thymic function can be partly replicated in vitro using OP9-DL1 cell cultures to yield CD8 αβ TCR-bearing cells from hematopoietic progenitor cells, a comprehensive and functional assessment of entirely in vitro generated CD8 T cells derived from bone marrow hematopoietic stem cells has not been established and remains controversial. In this study, we demonstrate that a phenotypic, molecular, and functional signature of in vitro derived CD8 T cells is akin to that of ex vivo CD8 T cells, although several significant differences were also observed. Transfer of in vitro derived CD8 T cells into syngeneic and immunodeficient host mice showed no graft-versus-host response, whereas a robust homeostatic proliferation was observed, respectively. These findings, along with a diverse and broad TCR repertoire expressed by the in vitro derived CD8 T cells, allowed for the successful generation of Ag-specific T cells to be obtained from an entirely in vitro generated CD8 T cell pool. These findings support the use of Ag-specific in vitro derived effector CD8 T cells for immune reconstitution approaches, which would be amenable to further tailoring for their use against viral infections or malignancies.

Authors
Dervovic, DD; Ciofani, M; Kianizad, K; Zúñiga-Pflücker, JC
MLA Citation
Dervovic, DD, Ciofani, M, Kianizad, K, and Zúñiga-Pflücker, JC. "Comparative and functional evaluation of in vitro generated to ex vivo CD8 T cells." J Immunol 189.7 (October 1, 2012): 3411-3420.
PMID
22925927
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
189
Issue
7
Publish Date
2012
Start Page
3411
End Page
3420
DOI
10.4049/jimmunol.1200979

Dynamic microRNA gene transcription and processing during T cell development.

By disrupting microRNA (miRNA) biogenesis, we previously showed that this pathway is critical for the differentiation and function of T cells. Although various cloning studies have shown that many miRNAs are expressed during T cell development, and in a dynamic manner, it was unclear how comprehensive these earlier analyses were. We therefore decided to profile miRNA expression by next generation sequencing. Furthermore, we profiled miRNA expression starting from the hematopoietic stem cell. This analysis revealed that miRNA expression during T cell development is extremely dynamic, with 645 miRNAs sequenced, and the expression of some varying by as much as 3 orders of magnitude. Furthermore, changes in precursor processing led to altered mature miRNA sequences. We also analyzed the structures of the primary miRNA transcripts expressed in T cells and found that many were extremely long. The longest was pri-mir-29b-1/29a at ∼168 kb. All the long pri-miRNAs also displayed extensive splicing. Our findings indicate that miRNA expression during T cell development is both a highly dynamic and a highly regulated process.

Authors
Kirigin, FF; Lindstedt, K; Sellars, M; Ciofani, M; Low, SL; Jones, L; Bell, F; Pauli, F; Bonneau, R; Myers, RM; Littman, DR; Chong, MMW
MLA Citation
Kirigin, FF, Lindstedt, K, Sellars, M, Ciofani, M, Low, SL, Jones, L, Bell, F, Pauli, F, Bonneau, R, Myers, RM, Littman, DR, and Chong, MMW. "Dynamic microRNA gene transcription and processing during T cell development." J Immunol 188.7 (April 1, 2012): 3257-3267.
PMID
22379031
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
188
Issue
7
Publish Date
2012
Start Page
3257
End Page
3267
DOI
10.4049/jimmunol.1103175

Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity.

CD4(+) T helper lymphocytes that express interleukin-17 (T(H)17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in T(H)17 cell differentiation and function with susceptibility to Crohn's disease, rheumatoid arthritis and psoriasis. Thus, the pathway towards differentiation of T(H)17 cells and, perhaps, of related innate lymphoid cells with similar effector functions, is an attractive target for therapeutic applications. Mouse and human T(H)17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORγt, which is required for induction of IL-17 transcription and for the manifestation of T(H)17-dependent autoimmune disease in mice. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORγt transcriptional activity. Digoxin inhibited murine T(H)17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives 20,22-dihydrodigoxin-21,23-diol and digoxin-21-salicylidene specifically inhibited induction of IL-17 in human CD4(+) T cells. Using these small-molecule compounds, we demonstrate that RORγt is important for the maintenance of IL-17 expression in mouse and human effector T cells. These data indicate that derivatives of digoxin can be used as chemical templates for the development of RORγt-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease.

Authors
Huh, JR; Leung, MWL; Huang, P; Ryan, DA; Krout, MR; Malapaka, RRV; Chow, J; Manel, N; Ciofani, M; Kim, SV; Cuesta, A; Santori, FR; Lafaille, JJ; Xu, HE; Gin, DY; Rastinejad, F; Littman, DR
MLA Citation
Huh, JR, Leung, MWL, Huang, P, Ryan, DA, Krout, MR, Malapaka, RRV, Chow, J, Manel, N, Ciofani, M, Kim, SV, Cuesta, A, Santori, FR, Lafaille, JJ, Xu, HE, Gin, DY, Rastinejad, F, and Littman, DR. "Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity." Nature 472.7344 (April 28, 2011): 486-490.
PMID
21441909
Source
pubmed
Published In
Nature
Volume
472
Issue
7344
Publish Date
2011
Start Page
486
End Page
490
DOI
10.1038/nature09978

Determining γδ versus αß T cell development.

The thymus produces several types of functionally distinct T cell subsets. However, at a more fundamental level only two genetically distinct T cell lineages exist: the γδ and αß T cell lineages. Precisely how these two T cell lineages are generated from common thymocyte progenitor cells remains to be fully elucidated and is under intense investigation. Here, we highlight recent findings that have helped to provide important clues to the mechanisms that underpin the generation of γδ T cells in the mouse thymus.

Authors
Ciofani, M; Zúñiga-Pflücker, JC
MLA Citation
Ciofani, M, and Zúñiga-Pflücker, JC. "Determining γδ versus αß T cell development." Nat Rev Immunol 10.9 (September 2010): 657-663. (Review)
PMID
20725107
Source
pubmed
Published In
Nature Reviews Immunology
Volume
10
Issue
9
Publish Date
2010
Start Page
657
End Page
663
DOI
10.1038/nri2820

Epigenetic propagation of CD4 expression is established by the Cd4 proximal enhancer in helper T cells.

The stability of a lineage program (cellular memory) is dependent on mechanisms that epigenetically maintain active or repressed states of gene expression (transcriptional memory). Although epigenetic silencing of genes has been clearly demonstrated from yeast to mammals, heritable maintenance of active transcription has been less clearly defined. To investigate the potential role of active transcriptional memory during lineage diversification, we employed targeted mutation of a positive-acting cis element in the Cd4 locus to determine the impact on CD4 expression and the differentiation of CD4(+) helper T cells in mice. We show that the proximal enhancer (E4(P)) of Cd4 is essential for CD4 expression in immature CD4(+)8(+) thymocytes. Furthermore, its loss resulted in reduced and unstable expression of CD4 in mature T cells. However, if the enhancer was deleted after cells had already committed to the helper T-cell lineage, CD4 expression remained high and was stable upon cell division. "Active" histone modifications, once initiated by E4(P), were also propagated independently of the enhancer. Thus, E4(P) is responsible for establishing an epigenetically inherited active Cd4 locus in the helper T-cell lineage. To our knowledge, this is the first genetic demonstration of active transcriptional memory in mammalian cells.

Authors
Chong, MMW; Simpson, N; Ciofani, M; Chen, G; Collins, A; Littman, DR
MLA Citation
Chong, MMW, Simpson, N, Ciofani, M, Chen, G, Collins, A, and Littman, DR. "Epigenetic propagation of CD4 expression is established by the Cd4 proximal enhancer in helper T cells." Genes Dev 24.7 (April 1, 2010): 659-669.
PMID
20360383
Source
pubmed
Published In
Genes & development
Volume
24
Issue
7
Publish Date
2010
Start Page
659
End Page
669
DOI
10.1101/gad.1901610

Marked induction of the helix-loop-helix protein Id3 promotes the gammadelta T cell fate and renders their functional maturation Notch independent.

alphabeta and gammadelta T cells arise from a common thymocyte progenitor during development in the thymus. Emerging evidence suggests that the pre-T cell receptor (pre-TCR) and gammadelta T cell receptor (gammadeltaTCR) play instructional roles in specifying the alphabeta and gammadelta T-lineage fates, respectively. Nevertheless, the signaling pathways differentially engaged to specify fate and promote the development of these lineages remain poorly understood. Here, we show that differential activation of the extracellular signal-related kinase (ERK)-early growth response gene (Egr)-inhibitor of DNA binding 3 (Id3) pathway plays a defining role in this process. In particular, Id3 expression served to regulate adoption of the gammadelta fate. Moreover, Id3 was both necessary and sufficient to enable gammadelta-lineage cells to differentiate independently of Notch signaling and become competent IFNgamma-producing effectors. Taken together, these findings identify Id3 as a central player that controls both adoption of the gammadelta fate and its maturation in the thymus.

Authors
Lauritsen, JPH; Wong, GW; Lee, S-Y; Lefebvre, JM; Ciofani, M; Rhodes, M; Kappes, DJ; Zúñiga-Pflücker, JC; Wiest, DL
MLA Citation
Lauritsen, JPH, Wong, GW, Lee, S-Y, Lefebvre, JM, Ciofani, M, Rhodes, M, Kappes, DJ, Zúñiga-Pflücker, JC, and Wiest, DL. "Marked induction of the helix-loop-helix protein Id3 promotes the gammadelta T cell fate and renders their functional maturation Notch independent." Immunity 31.4 (October 16, 2009): 565-575.
PMID
19833086
Source
pubmed
Published In
Immunity
Volume
31
Issue
4
Publish Date
2009
Start Page
565
End Page
575
DOI
10.1016/j.immuni.2009.07.010

Early growth response 1 and NF-ATc1 act in concert to promote thymocyte development beyond the beta-selection checkpoint.

Development of immature T cell precursors beyond the beta-selection checkpoint is regulated by signals transduced by the pre-TCR complex. The pre-TCR-induced differentiation program is orchestrated by a network of transcription factors that serve to integrate this signaling information. Among these transcription factors are those of the early growth response (Egr) and NF-AT families. In this study, we demonstrate that Egr1 and NF-ATc1 act together to promote development of T cell precursors beyond the beta-selection checkpoint to the CD8 immature single-positive and CD4+ CD8+ double-positive stages. Moreover, we find that Egr1 and NF-AT cooperatively induce the expression of inhibitor of DNA binding 3 (Id3), a regulatory factor known to play an important role in positive selection of thymocytes, but not previously demonstrated to be required for beta-selection. Importantly, we show in this study that Id3 deficiency abrogates the ability of ectopically expressed Egr1 to promote traversal of the beta-selection checkpoint. Id3 is presumably essential for traversal of the beta-selection checkpoint in this context because of the inability of other inhibitor of DNA binding family members to compensate, since transgenic Egr1 does not induce expression of inhibitor of DNA binding 1 (Id1) or 2 (Id2). Taken together, these data demonstrate that Id3 is a cooperatively induced target that is important for Egr-mediated promotion of development beyond the beta-selection checkpoint. Moreover, these data indicate that the ERK and calcium signaling pathways may converge during beta-selection through the concerted action of Egr1 and NF-ATc1, respectively.

Authors
Koltsova, EK; Ciofani, M; Benezra, R; Miyazaki, T; Clipstone, N; Zúñiga-Pflücker, JC; Wiest, DL
MLA Citation
Koltsova, EK, Ciofani, M, Benezra, R, Miyazaki, T, Clipstone, N, Zúñiga-Pflücker, JC, and Wiest, DL. "Early growth response 1 and NF-ATc1 act in concert to promote thymocyte development beyond the beta-selection checkpoint." J Immunol 179.7 (October 1, 2007): 4694-4703.
PMID
17878368
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
179
Issue
7
Publish Date
2007
Start Page
4694
End Page
4703

Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.

Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.

Authors
Palomero, T; Sulis, ML; Cortina, M; Real, PJ; Barnes, K; Ciofani, M; Caparros, E; Buteau, J; Brown, K; Perkins, SL; Bhagat, G; Agarwal, AM; Basso, G; Castillo, M; Nagase, S; Cordon-Cardo, C; Parsons, R; Zúñiga-Pflücker, JC; Dominguez, M; Ferrando, AA
MLA Citation
Palomero, T, Sulis, ML, Cortina, M, Real, PJ, Barnes, K, Ciofani, M, Caparros, E, Buteau, J, Brown, K, Perkins, SL, Bhagat, G, Agarwal, AM, Basso, G, Castillo, M, Nagase, S, Cordon-Cardo, C, Parsons, R, Zúñiga-Pflücker, JC, Dominguez, M, and Ferrando, AA. "Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia." Nat Med 13.10 (October 2007): 1203-1210.
PMID
17873882
Source
pubmed
Published In
Nature Medicine
Volume
13
Issue
10
Publish Date
2007
Start Page
1203
End Page
1210
DOI
10.1038/nm1636

The thymus as an inductive site for T lymphopoiesis.

Like all hematopoietic cells, T lymphocytes are derived from bone-marrow-resident stem cells. However, whereas most blood lineages are generated within the marrow, the majority of T cell development occurs in a specialized organ, the thymus. This distinction underscores the unique capacity of the thymic microenvironment to support T lineage restriction and differentiation. Although the identity of many of the contributing thymus-derived signals is well established and rooted in highly conserved pathways involving Notch, morphogenetic, and protein tyrosine kinase signals, the manner in which the ensuing cascades are integrated to orchestrate the underlying processes of T cell development remains under investigation. This review focuses on the current definition of the early stages of T cell lymphopoiesis, with an emphasis on the nature of thymus-derived signals delivered to T cell progenitors that support the commitment and differentiation of T cells toward the alphabeta and gammadelta T cell lineages.

Authors
Ciofani, M; Zúñiga-Pflücker, JC
MLA Citation
Ciofani, M, and Zúñiga-Pflücker, JC. "The thymus as an inductive site for T lymphopoiesis." Annu Rev Cell Dev Biol 23 (2007): 463-493. (Review)
PMID
17506693
Source
pubmed
Published In
Annual Review of Cell and Developmental Biology
Volume
23
Publish Date
2007
Start Page
463
End Page
493
DOI
10.1146/annurev.cellbio.23.090506.123547

Stage-specific and differential notch dependency at the alphabeta and gammadelta T lineage bifurcation.

Signals transduced by Notch receptors are indispensable for T cell specification and differentiation of alphabeta T lineage cells. However, the role of Notch signals during alphabeta versus gammadelta T lineage decision remains controversial. Here, we addressed this question by employing a clonal analysis of CD4(-)CD8(-) (DN) progenitor potential to position the divergence of alphabeta and gammadelta T cell lineages to the late DN2 to DN3 developmental stages. Accordingly, alphabeta and gammadelta precursor frequencies within these T cell progenitor subsets were determined, both in the presence and absence of Notch signaling through Delta-like 1. Notch signals were found to be critical for the DN to CD4(+)CD8(+) (DP) transition, irrespective of the identity (pTalphabeta or gammadelta) of the inducing T cell receptor complex, whereas gammadelta T cells developed from gammadeltaTCR-expressing T cell progenitors in the absence of further Notch ligand interaction. Collectively, our findings demonstrate a differential, stage-specific requirement for Notch receptor-ligand interactions in the differentiation of alphabeta and gammadelta T cells from T cell progenitors.

Authors
Ciofani, M; Knowles, GC; Wiest, DL; von Boehmer, H; Zúñiga-Pflücker, JC
MLA Citation
Ciofani, M, Knowles, GC, Wiest, DL, von Boehmer, H, and Zúñiga-Pflücker, JC. "Stage-specific and differential notch dependency at the alphabeta and gammadelta T lineage bifurcation." Immunity 25.1 (July 2006): 105-116.
PMID
16814577
Source
pubmed
Published In
Immunity
Volume
25
Issue
1
Publish Date
2006
Start Page
105
End Page
116
DOI
10.1016/j.immuni.2006.05.010

Pre-T cell receptor's clashing signals: "should I stay or should I go".

In this issue of Immunity, Kersh and colleagues (Xi et al., 2006) investigate the regulatory network that permits two otherwise clashing cellular processes--proliferation and gene rearrangement--to occur at temporally distinct periods following the formation of the pre-T cell receptor (pre-TCR) complex.

Authors
Zúñiga-Pflücker, JC; Ciofani, M
MLA Citation
Zúñiga-Pflücker, JC, and Ciofani, M. "Pre-T cell receptor's clashing signals: "should I stay or should I go"." Immunity 24.6 (June 2006): 669-670. (Review)
PMID
16782022
Source
pubmed
Published In
Immunity
Volume
24
Issue
6
Publish Date
2006
Start Page
669
End Page
670
DOI
10.1016/j.immuni.2006.06.006

A survival guide to early T cell development.

The survival of immature T cell precursors is dependent on both thymus-derived extrinsic signals and self-autonomous pre-TCR-mediated signals. While the role of cytokines and the pre-TCR in promoting thymocyte survival has been well established, the relationship between pro- and anti-apoptotic signaling cascades remains poorly defined. Recent studies have established a link between cell survival and growth factor-mediated maintenance of cellular metabolism. In this regard, the Notch signaling pathway has emerged as more than an inducer of T lineage commitment and differentiation, but also as a potent trophic factor, promoting the survival and metabolic state of pre-T cells. In this review, we describe current concepts of the intracellular signaling pathways downstream of cell intrinsic and extrinsic factors that dictate survival versus death outcomes during early T cell development.

Authors
Ciofani, M; Zúñiga-Pflücker, JC
MLA Citation
Ciofani, M, and Zúñiga-Pflücker, JC. "A survival guide to early T cell development." Immunol Res 34.2 (2006): 117-132. (Review)
PMID
16760572
Source
pubmed
Published In
Immunologic Research
Volume
34
Issue
2
Publish Date
2006
Start Page
117
End Page
132
DOI
10.1385/IR:34:2:117

Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism

Authors
CIOFANI, M
MLA Citation
CIOFANI, M. "Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism." Nat Immunol. 6.9 (2005): 881-888.
PMID
16056227
Source
cinii-english
Published In
Nat Immunol.
Volume
6
Issue
9
Publish Date
2005
Start Page
881
End Page
888
DOI
10.1038/ni1234

Maintenance of T cell specification and differentiation requires recurrent notch receptor-ligand interactions.

Notch signaling has been shown to play a pivotal role in inducing T lineage commitment. However, T cell progenitors are known to retain other lineage potential long after the first point at which Notch signaling is required. Thus, additional requirements for Notch signals and the timing of these events relative to intrathymic differentiation remain unknown. Here, we address this issue by culturing subsets of CD4 CD8 double negative (DN) thymocytes on control stromal cells or stromal cells expressing Delta-like 1 (Dll1). All DN subsets were found to require Notch signals to differentiate into CD4+ CD8+ T cells. Using clonal analyses, we show that CD44+ CD25+ (DN2) cells, which appeared committed to the T cell lineage when cultured on Dll1-expressing stromal cells, nonetheless gave rise to natural killer cells with a progenitor frequency similar to that of CD44+ CD25- (DN1) thymocytes when Notch signaling was absent. These data, together with the observation that Dll1 is expressed on stromal cells throughout the thymic cortex, indicates that Notch receptor-ligand interactions are necessary for induction and maintenance of T cell lineage specification at both the DN1 and DN2 stages of T cell development, suggesting that the Notch-induced repression of the B cell fate is temporally separate from Notch-induced commitment to the T lineage.

Authors
Schmitt, TM; Ciofani, M; Petrie, HT; Zúñiga-Pflücker, JC
MLA Citation
Schmitt, TM, Ciofani, M, Petrie, HT, and Zúñiga-Pflücker, JC. "Maintenance of T cell specification and differentiation requires recurrent notch receptor-ligand interactions." J Exp Med 200.4 (August 16, 2004): 469-479.
PMID
15314075
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
200
Issue
4
Publish Date
2004
Start Page
469
End Page
479
DOI
10.1084/jem.20040394

Obligatory role for cooperative signaling by pre-TCR and Notch during thymocyte differentiation.

The first checkpoint during T cell development, known as beta selection, requires the successful rearrangement of the TCR-beta gene locus. Notch signaling has been implicated in various stages during T lymphopoiesis. However, it is unclear whether Notch receptor-ligand interactions are necessary during beta selection. Here, we show that pre-TCR signaling concurrent with Notch receptor and Delta-like-1 ligand interactions are required for the survival, proliferation, and differentiation of mouse CD4(-)CD8(-) thymocytes to the CD4(+)CD8(+) stage. Furthermore, we address the minimal signaling requirements underlying beta selection and show a hierarchical positioning of key proximal signaling molecules. Collectively, our results demonstrate an essential role for Notch receptor-ligand interactions in enabling the autonomous signaling capacity of the pre-TCR complex.

Authors
Ciofani, M; Schmitt, TM; Ciofani, A; Michie, AM; Cuburu, N; Aublin, A; Maryanski, JL; Zúñiga-Pflücker, JC
MLA Citation
Ciofani, M, Schmitt, TM, Ciofani, A, Michie, AM, Cuburu, N, Aublin, A, Maryanski, JL, and Zúñiga-Pflücker, JC. "Obligatory role for cooperative signaling by pre-TCR and Notch during thymocyte differentiation." J Immunol 172.9 (May 1, 2004): 5230-5239.
PMID
15100261
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
172
Issue
9
Publish Date
2004
Start Page
5230
End Page
5239
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Research Areas:

  • Animals
  • Antigens, CD4
  • Autoimmune Diseases
  • Autoimmunity
  • Basic-Leucine Zipper Transcription Factors
  • Bone Marrow Cells
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Cell Aging
  • Cell Cycle
  • Cell Death
  • Cell Differentiation
  • Cell Division
  • Cell Line
  • Cell Lineage
  • Cell Survival
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Cloning, Molecular
  • Coculture Techniques
  • Cytokines
  • Cytotoxicity Tests, Immunologic
  • DEAD-box RNA Helicases
  • DNA Mutational Analysis
  • DNA-Binding Proteins
  • Developmental Biology
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins
  • Early Growth Response Protein 1
  • Encephalomyelitis, Autoimmune, Experimental
  • Enhancer Elements, Genetic
  • Enzyme Activation
  • Epigenesis, Genetic
  • Epitopes
  • Extracellular Signal-Regulated MAP Kinases
  • Female
  • Fetus
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Fos-Related Antigen-2
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Expression Regulation, Leukemic
  • Gene Library
  • Gene Rearrangement
  • Gene Regulatory Networks
  • Genome-Wide Association Study
  • Hematopoietic Stem Cells
  • Hepatocytes
  • Humans
  • Immunomodulation
  • Inhibitor of Apoptosis Proteins
  • Inhibitor of Differentiation Proteins
  • Interferon Regulatory Factors
  • Intracellular Signaling Peptides and Proteins
  • Kinetics
  • Leukemia, T-Cell
  • Ligands
  • Lymphocyte Activation
  • Lymphoid Progenitor Cells
  • Lymphopoiesis
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • MicroRNAs
  • Microtubule-Associated Proteins
  • Models, Genetic
  • Molecular Sequence Data
  • Mutation
  • Neoplasm Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Organ Culture Techniques
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Pregnancy
  • Protein Isoforms
  • Protein Precursors
  • Proto-Oncogene Proteins c-akt
  • RGS Proteins
  • RNA Precursors
  • RNA Processing, Post-Transcriptional
  • Receptor, Notch1
  • Receptors, Antigen, T-Cell
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Notch
  • Regulatory Elements, Transcriptional
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonuclease III
  • Sequence Analysis, RNA
  • Signal Transduction
  • Stem Cells
  • Stromal Cells
  • Systems Biology
  • T-Lymphocyte Subsets
  • T-Lymphocytes
  • T-Lymphocytes, Helper-Inducer
  • Th17 Cells
  • Thymus Gland
  • Transcription Factor AP-1
  • Transcription Factors
  • Transcription, Genetic
  • Transcriptional Activation
  • Transgenes
  • Tumor Suppressor Protein p53