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, 32 (9), 395-401

T Helper 17 Cell Heterogeneity and Pathogenicity in Autoimmune Disease


T Helper 17 Cell Heterogeneity and Pathogenicity in Autoimmune Disease

Kamran Ghoreschi et al. Trends Immunol.


T helper (Th)17 cells have been proposed to represent a new CD4(+) T cell lineage that is important for host defense against fungi and extracellular bacteria, and the development of autoimmune diseases. Precisely how these cells arise has been the subject of some debate, with apparent species-specific differences in mice and humans. Here, we describe evolving views of Th17 specification, highlighting the contribution of transforming growth factor-β and the opposing roles of signal transducer and activator of transcription (STAT)3 and STAT5. Increasing evidence points to heterogeneity and inherent phenotypic instability in this subset. Ideally, better understanding of expression and action of key transcription factors and the epigenetic landscape of Th17 can help explain the flexibility and diversity of interleukin-17-producing cells.


Figure 1
Figure 1. Heterogeneity of Th17 cells
The conventional mode of inducing Th17 differentiation is to culture cells with IL-6, IL-1β and TGF-β. IL-6 acts to upregulate IL-23R and IL-21 expression. Subsequently, IL-6, IL-21 and IL-23, acting through STAT3, directly regulate many of the phenotype-defining Th17 genes. Though low levels of TGF-β clearly promote IL-17 production (a), a major unresolved question is its mechanism of action with respect to this cytokine. One can view TGF-β as providing an important positive instructive signal. However, TGF-β is not required to induce IL-23R expression. In addition, it is possible to generate Th17 cells with little or no TGF-β (b). Thus, an alternative explanation is that the major action of TGF-β is to inhibit IL-2, IFN-γ, T-bet and other factors that antagonize IL-17 production (c). Of note is that Th17 cells generated with little or no TGF-β are phenotypically and functionally distinct from conventional Th17 cells in terms of the transcription factors they express and the cytokines they produce. Also, Th17 cells are inherently unstable and can readily express IFN-γ, which further inhibits IL-17 production. Precisely, what the in vivo correlates of these different populations of Th17 cells are has not been defined exactly. However, in sites of autoimmune-mediated damage, cells that express RORγt and T-bet are present (d). IL-2 is key factor that negatively regulates IL-17 production. The inhibition of IL-17 by IL-2 is mediated through STAT5, which can directly compete with STAT3 to limit Il17 transcription. Tregs can provide TGF-β for IL-17 production, but more importantly promote Th17 cell differentiation by consuming IL-2 (e). Therefore, Treg participate in host defense and pathogen clearance by inducing IL-17.

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