Yonsei Med J.  2010 Jul;51(4):484-491. 10.3349/ymj.2010.51.4.484.

Transcriptional Regulation of T Helper 17 Cell Differentiation

• Hwang ES

• KMID: 1805183
• DOI: http://doi.org/10.3349/ymj.2010.51.4.484

Abstract

The third lineage of T helper subsets, Th17, has recently been identified as an IL-17-producing CD4+ Th cell, and its functions and regulatory mechanisms have been extensively characterized in immune responses. Functional studies have provided evidence that Th17 cells are important for the modulation of autoimmune responses, such as chronic asthma, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis. Murine Th17 cell differentiation is enhanced by the coordinated functions of distinct cytokines including TGFbeta, IL-6, IL-21, and IL-23, whereas IL-2, IL-4, IFNgamma, and IL-27 inhibit its differentiation. In addition, Th17 cells are controlled by several transcription factors such as RORgamma t, IRF4, BATF, FoxP3, T-bet, PPARgamma, E-FABP, and SOCSs. This review focuses on the functions and regulatory mechanisms of several transcription factors in the control of Th17 cell differentiation.

Keyword

T helper 17; TGFbeta; IL-6; transcription factor

Figure

• 

  Fig. 1 Cytokine signaling and transcription factors in the regulation of Th17 cell differentiation. TCR stimulation activates gene expression of general transcription factors such as NFAT, AP-1, and NF-κB, and induces Th cell activation and proliferation. BATF is activated upon TCR stimulation and stimulates IL-17 gene transcription. TGFβ stimulation induces both FoxP3 and RORγt (also RORa) activation. High concentrations of TGFb increase FoxP3 through the activation of SMAD4 and subsequently induce TGFb production and simultaneously suppress RORγt activity and Th17 cell differentiation. However, the presence of cytokine IL-6 or IL-21 activates STAT3 and induces gene expression of the IL-21 and IL-23 receptor, activating positive IL-21 autocrine regulation for Th17 cell differentiation. In addition, IL-1 induces IRF4 or epidermal FABP4, which in turn induces IL-17 gene transcription. While T-bet and Ets-1 antagonize RORγt activity and thus function as suppressors of Th17 cell development, PPARγ intrinsically suppresses IL-17 gene transcription by blocking the activation-induced removal of repressor complexes from the IL-17 gene promoter. SOCS1 and SOCS reciprocally modulate Th17 cell differentiation. TCR, T cell receptor; NFAT, nuclear factor of activated T cells; AP, activator protein; BATF, B cell-activating transcription factor; IL-17, interleukin-17; TGFβ, transforming growth factor β; RORγt, retinoic acid-related orphan receptor γt; STAT, signal transducer and activator of transcription; IRF-4, interferon-inducible factor-4; E-FABP, epidermal-fatty acid-binding protein; PPARγ, peroxisome proliferator activated receptor γ; SOCS, suppressors of cytokine signaling.

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