TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.
Liang Zhou,Jared E. Lopes,Jared E. Lopes,Mark M.W. Chong,Ivaylo I. Ivanov,Roy Min,Gabriel D. Victora,Yuelei Shen,Jianguang Du,Jianguang Du,Yuri P. Rubtsov,Alexander Y. Rudensky,Steven F. Ziegler,Steven F. Ziegler,Dan R. Littman +14 more
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TLDR
In this article, the authors demonstrate that, together with pro-inflammatory cytokines, TGF-beta orchestrates T helper cells that produce IL-17 (T(H)17 cells) in a concentration-dependent manner.Abstract:
T helper cells that produce IL-17 (T(H)17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, T(H)17 cells are thought to protect the host from infection, whereas regulatory T (T(reg)) cells control immune responses and inflammation triggered by the resident microflora. Differentiation of both cell types requires transforming growth factor-beta (TGF-beta), but depends on distinct transcription factors: RORgammat (encoded by Rorc(gammat)) for T(H)17 cells and Foxp3 for T(reg) cells. How TGF-beta regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro-inflammatory cytokines, TGF-beta orchestrates T(H)17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-beta synergizes with interleukin (IL)-6 and IL-21 (refs 9-11) to promote IL-23 receptor (Il23r) expression, favouring T(H)17 cell differentiation. High concentrations of TGF-beta repress IL23r expression and favour Foxp3+ T(reg) cells. RORgammat and Foxp3 are co-expressed in naive CD4+ T cells exposed to TGF-beta and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF-beta-induced Foxp3 inhibits RORgammat function, at least in part through their interaction. Accordingly, lamina propria T cells that co-express both transcription factors produce less IL-17 (also known as IL-17a) than those that express RORgammat alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORgammat, thereby promoting T(H)17 cell differentiation. Therefore, the decision of antigen-stimulated cells to differentiate into either T(H)17 or T(reg) cells depends on the cytokine-regulated balance of RORgammat and Foxp3.read more
Citations
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Journal ArticleDOI
IL-17 and Th17 Cells.
TL;DR: The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation and now appreciate the importance of Th 17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.
Journal ArticleDOI
The gut microbiota shapes intestinal immune responses during health and disease
TL;DR: Findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut are discussed, and the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms is raised.
Journal ArticleDOI
Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria
Ivaylo I. Ivanov,Koji Atarashi,Nicolas Manel,Eoin L. Brodie,Tatsuichiro Shima,Ulas Karaoz,Dongguang Wei,Katherine C. Goldfarb,Clark A. Santee,Susan V. Lynch,Takeshi Tanoue,Akemi Imaoka,Kikuji Itoh,Kiyoshi Takeda,Yoshinori Umesaki,Kenya Honda,Dan R. Littman +16 more
TL;DR: The authors showed that colonisation of mice with a segmented filamentous bacterium (SFB) is sufficient to induce the appearance of CD4+ T helper cells that produce IL-17 and IL-22 (Th17 cells) in the lamina propria.
Journal ArticleDOI
Differentiation of Effector CD4 T Cell Populations
TL;DR: This review summarizes the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.
Journal ArticleDOI
TGFβ signalling in context.
TL;DR: The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed and the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings.
References
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Journal ArticleDOI
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
Estelle Bettelli,Yijun Carrier,Wenda Gao,Thomas Korn,Terry B. Strom,Mohamed Oukka,Howard L. Weiner,Vijay K. Kuchroo +7 more
TL;DR: It is shown that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ Treg cells induced by TGF-β, and the data demonstrate a dichotomy in thegeneration of pathogenic (TH17) T cells that induce autoimmunity and regulatory (Foxp3+) T Cells that inhibit autoimmune tissue injury.
Journal ArticleDOI
Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3
Wanjun Chen,Wenwen Jin,Neil J. Hardegen,Ke Jian Lei,Li Li,Nancy J. Marinos,George McGrady,Sharon M. Wahl +7 more
TL;DR: Novel evidence is presented that conversion of naive peripheral CD4+CD25− T cells into anergic/suppressor cells that are CD25+, CD45RB−/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor β (TGF-β).
Journal ArticleDOI
The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.
Ivaylo I. Ivanov,Brent S. McKenzie,Liang Zhou,Carlos E. Tadokoro,Alice Lepelley,Juan J. Lafaille,Daniel J. Cua,Dan R. Littman +7 more
TL;DR: It is shown that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage of proinflammatory T helper cells and its potential as a therapeutic target in inflammatory diseases is highlighted.
Journal ArticleDOI
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
Claire L. Langrish,Yi Yi Chen,Wendy M. Blumenschein,Jeanine D. Mattson,Beth Basham,Jonathan D. Sedgwick,Terrill K. McClanahan,Robert A. Kastelein,Daniel J. Cua +8 more
TL;DR: Using passive transfer studies, it is confirmed that these IL-23–dependent CD4+ T cells are highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity.
Journal ArticleDOI
TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-Producing T cells
Marc Veldhoen,Richard J. Hocking,Christopher J. Atkins,Richard M. Locksley,Brigitta Stockinger +4 more
TL;DR: The data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation ofIL-17-producing T cells.