Transcription Factor IRF8 Directs a Silencing Programme for TH17 Cell Differentiation

Abstract

T(_H)17 cells are recognized as a unique subset of T helper cells that have critical roles in the pathogenesis of autoimmunity and tissue inflammation. Although RORγt is necessary for the generation of T(_H)17 cells, the molecular mechanisms underlying the functional diversity of T(_H)17 cells are not fully understood. Here we show that a member of interferon regulatory factor (IRF) family of transcription factors, IRF8, has a critical role in silencing T(_H)17-cell differentiation. Mice with a conventional knockout, as well as a T cell-specific deletion, of the Irf8 gene exhibited more efficient T(_H)17 cells. Indeed, studies of an experimental model of colitis showed that IRF8 deficiency resulted in more severe inflammation with an enhanced T(_H)17 phenotype. IRF8 was induced steadily and inhibited T(_H)17-cell differentiation during T(_H)17 lineage commitment at least in part through its physical interaction with RORγt. These findings define IRF8 as a novel intrinsic transcriptional inhibitor of T(_H)17-cell differentiation.