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Abstract: Interleukin-17A (IL-17A) is the signature cytokine produced by Th17 CD4+ T cells and has been tightly linked to autoimmune pathogenesis. In particular, the transcription factors NFAT and RORγt are known to activate Il17a transcription, although the detailed mechanism of action remains incompletely understood. Here, we show that the nuclear orphan receptor NR2F6 can attenuate the capacity of NFAT to bind to critical regions of the Il17a gene promoter. In addition, because NR2F6 binds to defined hormone response elements (HREs) within the Il17a locus, it interferes with the ability of RORγt to access the DNA. Consistently, NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4+ Th17 cells but decreased in Nr2f6-overexpressing transgenic CD4+ Th17 cells. Taken together, our findings uncover an example of antagonistic regulation of Il17a transcription through the direct reciprocal actions of NR2F6 versus NFAT and RORγt. [Copyright &y& Elsevier]

Abstract: Transforming growth factor β (TGFβ) plays a central role in maintaining immune homeostasis by regulating the initiation and termination of immune responses and thus preventing the development of autoimmune diseases. In this study, we describe an essential mechanism by which the actin regulatory protein Coronin 1A (Coro1A) ensures the proper response of Th17 CD4+ T cells to TGFβ. Coro1A has been established as a key player in T cell survival, migration, activation, and Ca2+ regulation in naive T cells. We show that mice lacking Coro1a developed less severe experimental autoimmune encephalomyelitis (EAE). Unexpectedly, upon the re-induction of EAE, Coro1a −/− mice exhibited enhanced EAE signs that correlated with increased numbers of IL-17 producing CD4+ cells in the central nervous system (CNS) compared to wild-type mice. In vitro differentiated Coro1a −/− Th17 CD4+ T cells consistently produced more IL-17 than wild-type cells and displayed a Th17/Th1-like phenotype in regard to the expression of the Th1 markers T-bet and IFNγ. Mechanistically, the Coro1a −/− Th17 cell phenotype correlated with a severe defect in TGFβR-mediated SMAD3 activation. Taken together, these data provide experimental evidence of a non-redundant role of Coro1A in the regulation of Th17 CD4+ cell effector functions and, subsequently, in the development of autoimmunity. [Copyright &y& Elsevier]