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, 19 (6), 400-8

Signal Transduction Pathways and Transcriptional Regulation in the Control of Th17 Differentiation


Signal Transduction Pathways and Transcriptional Regulation in the Control of Th17 Differentiation

Zhi Chen et al. Semin Immunol.


The discovery of a new lineage of helper T cells that selectively produces interleukin (IL)-17 has provided exciting new insights into immunoregulation, host defense and the pathogenesis of autoimmune diseases. Additionally, the discovery of this T cell subset has offered a fresh look at how the complexity of selective regulation of cytokine gene expression might relate to lineage commitment, terminal differentiation and immunologic memory. Information continues to accumulate on factors that regulate Th17 differentiation at a rapid pace and a few lessons have emerged. Like other lineages, Th17 cells preferentially express a transcription factor, retinoic acid-related orphan receptor (ROR)gammat, whose expression seems to be necessary for IL-17 production. In addition, signals from the T-cell receptor are a critical aspect of controlling IL-17 production and the transcription factor nuclear factor of activated T cells (NFATs) appears to be another important regulator. IL-6, IL-21 and IL-23 are all cytokines that activate the transcription factor STAT3, which has been established to be necessary for multiple aspects of the biology of Th17 cells. Similarly, TGFbeta-1 is important for the differentiation of murine Th17 cells and inducible regulatory T cells (iTregs), but how it exerts its effect on IL-17 gene transcription is unknown and there are data indicating TGFbeta-1 is not required for human Th17 differentiation. The extent to which Th17 cells represent terminally differentiated cells or whether they retain plasticity and can develop into another lineage such as IFNgamma secreting Th1 cells is also unclear. Precisely how cytokines produced by this lineage are selectively expressed and selectively extinguished through epigenetic modifications is an area of great importance, but considerable uncertainty.


Figure 1
Figure 1. Signaling pathways and transcription factors that regulate Th17 differentiation
In helper T cells, TCR stimulation activates NFAT, which likely directly regulates IL17 expression. Cytokines such IL-6, IL-21 and IL-23, activate STAT3, which also binds Il17a/f, and Il21 genes and controls Rorc and Il23r expression. TGFβ-1 signaling involves the activation of SMAD proteins. This cytokine acts in conjunction with STAT3 and Rorγt, although the mechanism through which TGFβ-1 promotes differentiation of Th17 cells is presently unknown. IRF4 is also a positive regulator of Th17 differentiation, how it acts is unclear. Unsurprisingly, many factors inhibit Th17 differentiation. Retinoic acid, acting through its cognate receptors, downregulates IL-17 expression and upregulates Foxp3 expression. IL-2, IL-4, IFNγ and IL-27 activate STAT5, STAT6 and STAT1, respectively, also negatively regulate Il17a expression. Foxp3 also inhibits cytokine production.

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