Transcriptional regulation of Th17 cell differentiation

doi:10.1016/j.smim.2007.10.011

Seminars in Immunology

Volume 19, Issue 6, December 2007, Pages 409-417

https://doi.org/10.1016/j.smim.2007.10.011 Get rights and content

Abstract

The paradigm of effector T helper cell differentiation into either Th1 or Th2 lineages has been profoundly shaken by the discovery of T cells that secrete IL-17 and other inflammatory cytokines. This subset, referred to as Th17, is centrally involved in autoimmune disease and is important in host defense at mucosal surfaces. In mouse, a series of cytokines, including IL-6, IL-21, IL-23, and TGF-β, function sequentially or synergistically to induce the Th17 lineage. Other cytokines, including IL-2, IL-4, IFNγ, and IL-27, inhibit differentiation of this lineage. Here we review how the nuclear orphan receptor RORγt functions to coordinate the diverse cytokine-induced signals and thus controls Th17 cell differentiation.

Introduction

T helper (Th) cells with diverse effector functions differentiate from naïve CD4⁺ T cells upon stimulation by antigen in the presence of different cytokines produced by cells of the innate immune system. Until recently, two major cell subsets, Th1 and Th2, were known to provide effector responses to intracellular and extracellular pathogens, respectively, through the production of specific cytokines. Th1 cells produce interferon-γ (IFNγ) and lymphotoxin-α (LTα) while Th2 cells produce interleukin-4 (IL-4), IL-5, IL-13, and other cytokines [1]. Th1 cells, which require IL-12 for their differentiation, had been thought to mediate a series of autoimmune conditions. However, recent studies have clearly shown that T helper lymphocytes that require the IL-12 family member IL-23 to differentiate and secrete pro-inflammatory cytokines, rather than Th1 cells, are major mediators of inflammatory responses in most of these “Th1” autoimmune diseases [2], [3], [4], [5], [6]. These cells produce IL-17, IL-17F, IL-21, and IL-22, and are now recognized as belonging to a distinct effector cell subset, the Th17 cells [7]. Our understanding of the normal functions of Th17 cells remains sketchy, although it is thought that they have key roles in providing immunity to various bacteria and fungi, particularly at mucosal surfaces.

In this review, we discuss our current understanding of the regulation of Th17 cell differentiation, with a focus on the cytokine and transcription factor requirements both in vivo and in vitro. We also describe the distribution and potential functions of Th17 cells at sites within the body that are in contact with commensal microorganisms, and focus on the relationship between Foxp3⁺ regulatory T cells and Th17 cells in such tissues.

Section snippets

Th17-inducing cytokine environment

Although the cytokine IL-17 had been known for some time to have potent pro-inflammatory activity [8], appreciation of its role in inflammatory T cell-mediated autoimmune diseases has come only recently. The key finding in this field was the observation that mice deficient for the p19 subunit of IL-23, a cytokine that shares its other subunit (p40) with IL-12, are resistant to induction of experimental autoimmune encephalomyelitis (EAE) due to lack of IL-17-producing T cells [2], [3]. Other

RORγt: a master regulator of the Th17 cell lineage?

Two independent approaches led to the identification of the retinoic acid-related orphan receptor (ROR)γt as the key transcription factor in the differentiation program of Th17 cells. Genome-wide expression profiling of antigen-stimulated splenocytes revealed up-regulation of RORγt mRNA in response to IL-23 and, in a mouse strain engineered such that RORγt-expressing cells also expressed green fluorescent protein (GFP), most GFP⁺ T cells, and only a few of the GFP⁻ T cells, expressed

Sequential cytokine function in Th17 cell differentiation: Roles of IL-21 and IL-23

Recent studies have begun to shed some light on why IL-23 is required in vivo, but not in vitro, for Th17 cell differentiation. The function of IL-23 appears to be dependent, at least in part, on another cytokine, IL-21, that is mainly produced by activated CD4⁺ T cells and activates, through a receptor that contains the common γ chain (γ_c), the STAT1/STAT3 pathway [24], [25]. The mRNA for IL-21 was identified as one of the most highly induced transcripts in expression profile analyses of

Cytokine-mediated inhibition of the Th17 cell differentiation program

Th17 cells can develop independently of the transcription factors STAT1, T-bet, STAT4 and STAT6, indicating that they represent a distinct T helper cell lineage [37], [38]. The Th1 cytokine IFNγ and Th2 cytokines (e.g. IL-4) were the first shown to inhibit the differentiation of the Th17 lineage [39]. Neutralization of IFNγ and IL-4 increased IL-17 expression in cell culture systems. Mice lacking T-bet, a T-box transcription factor required for Th1 cell differentiation and IFNγ production,

Regulation of Th17 cell differentiation by a balance of RORγt and Foxp3

TGF-β alone induces the expression of both Foxp3 and RORγt in TCR-stimulated naïve CD4⁺ T cells [26]. Despite its induction of RORγt, TGF-β is unable to initiate Th17 differentiation in vitro unless pro-inflammatory cytokines, such as IL-6 or IL-21, are also present. This appears to be due to a Foxp3-mediated inhibition of the activity of RORγt, resulting in abrogation of IL-17 and IL-23R expression in the absence of the pro-inflammatory cytokines (Liang Zhou et al., submitted). In humans, two

IRF4: another transcription factor required for Th17 cell differentiation

Most recently, IRF4, a transcription factor previously shown to be important for Th2 cell differentiation, was discovered to also be essential for Th17 cell differentiation [52]. IRF4-deficient mice were protected from EAE and T cells from these animals failed to differentiate into Th17 cells. Furthermore, IRF4-deficient T cells had less RORγt expression and more Foxp3 expression, again highlighting the importance of the RORγt-Foxp3 balance in Th17 cell development. RORγt induction was impaired

In vivo development and function of Th17 cells

In wildtype unimmunized mice kept under SPF conditions, CD4⁺ IL-17-producing Th17 cells are present almost exclusively in the small intestinal LP and other mucosal tissues ([12] and Ivaylo I. Ivanov and Dan R. Littman, unpublished data). This observation suggests that Th17 cells are specialized to handle the unique challenges presented to the immune system in the intestine. The mucosal immune system must maintain tolerance towards the enormous number of resident microbial species and the

Th17 cells in human versus mouse

The Th17 cell differentiation pathway is now recognized as having a key role in a variety of human autoimmune diseases. However, our understanding of human Th17 cell differentiation has lagged behind that of its mouse counterpart. Differences in the pathway between mouse and human T cells have been described, but it has been difficult to interpret these, because the human T cells analyzed are generally antigen-experienced cells, whereas most murine studies have relied on naïve T cells. With

Conclusions

Th17 cells are now thought to have key roles in a variety of human autoimmune diseases, including psoriasis, rheumatoid arthritis, and Crohn's disease. Polymorphisms in the gene encoding IL-23R have been found in strong association with susceptibility or resistance to Crohn's disease [68], thus providing genetic validation for the Th17 cell differentiation pathway in this disease. Substantial progress has been made in elucidating the cytokine signals and transcription factors that specify the

Acknowledgements

This work was supported by fellowships from the Crohn's and Colitis Foundation of America and the Irvington Institute to III and LZ, respectively, by NIH grant RO1 AI033856-14 (DRL), and by the Howard Hughes Medical Institute (DRL).

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ReviewTranscriptional regulation of Th17 cell differentiation

Abstract

Introduction

Section snippets

Th17-inducing cytokine environment

RORγt: a master regulator of the Th17 cell lineage?

Sequential cytokine function in Th17 cell differentiation: Roles of IL-21 and IL-23

Cytokine-mediated inhibition of the Th17 cell differentiation program

Regulation of Th17 cell differentiation by a balance of RORγt and Foxp3

IRF4: another transcription factor required for Th17 cell differentiation

In vivo development and function of Th17 cells

Th17 cells in human versus mouse

Conclusions

Acknowledgements

Immunity

Immunity

Cell

Cell

Immunity

Genomics

Gene

Biochem Biophys Res Commun

Prog Nucleic Acid Res Mol Biol

J Biol Chem

J Biol Chem

Immunity

J Biol Chem

Curr Opin Immunol

Blood

Cell

Immunity

Curr Opin Cell Biol

TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties

Annu Rev Immunol

Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

Nature

IL-23 drives a pathogenic T cell population that induces autoimmune inflammation

J Exp Med

Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation

J Exp Med

Interleukin-23 drives innate and T cell-mediated intestinal inflammation

J Exp Med

IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis

J Exp Med

Th17: the third member of the effector T cell trilogy

Curr Opin Immunol

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

Nature

Transforming growth factor-beta induces development of the T(H)17 lineage

Nature

Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease

Nat Immunol

The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches

Immunol Rev

Requirement for RORgamma in thymocyte survival and lymphoid organ development

Science

Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells

Science

An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells

Nat Immunol

Biology of IL-21 and the IL-21 receptor

Immunol Rev

Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation

Nat Rev Immunol

Review
Transcriptional regulation of Th17 cell differentiation