Negative Regulation of TH17 Differentiation

Chapter

Abstract

TH17 cells and their associated cytokines act on resident parenchymal cells within tissues, thereby setting the stage for chronic inflammation. This realization, together with the finding that TH17 cell development is reciprocally linked to that of T regulatory (Treg) cells, has revolutionized the way T cell-mediated immune pathology is viewed, and challenged the long-standing binary view of T cell differentiation (i.e., TH1/TH2), thereby opening exciting new opportunities to treat auto-immune inflammation. Much effort is now placed on understanding how TH17 cells are restrained through endogenous mechanisms; the goal being to negatively regulate TH17 development or function in clinical disease settings. The TH1 and TH2 cytokines, IFNγ and IL-4, as well as IL-27 and IL-10, all repress TH17 cell differentiation. TGFβ signaling, which supports TH17 differentiation in some contexts, can also strongly induce expression of the signature regulatory T cell transcription factor, Foxp3, which in turn cripples TH17 differentiation through direct antagonism of the TH17-specific orphan nuclear receptor RORγt. Emerging evidence also suggests that TH17 cells are both inherently unstable and uniquely sensitive to metabolic stress. Here, we discuss some of the key molecular features of TH17 cell development and highlight examples of cell-intrinsic and cell-extrinsic pathways that negatively influence TH17 differentiation, the latter of which could be exploited for therapeutic application.

Keywords

Arthritis Mold Serine Arginine Tryptophan 

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pathology, Harvard Medical SchoolImmune Disease Institute and the Program in Cellular and Molecular Medicine at Children’s Hospital BostonBostonUSA
  2. 2.Tempero PharmaceuticalsCambridgeUSA

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