8: Epigenetic regulation of Th-17 differentiation

Abstract

Differentiation of Th17 cells requires the combination of IL-6 and TGF-β and is further maintained by IL-23. This T cell subtype is important for both host defense against extracellular pathogens and the pathogenesis of autoimmune diseases. The main cytokines produced by Th17 cells are IL-17, which induces strong proinflammatory effects, and IL-22, an enhancer of epithelial proliferation and healing responses. Previous research has demonstrated that the expression of the transcription factor c-Maf is important for inhibition of IL-22 production in Th17 cells. The transcription factor AHR (aryl hydrocarbon receptor) has also been shown crucial for proper Th17 differentiation. The adapter protein PTIP (Pax transactivation domain-interacting protein) has recently been shown to have a role in the maturation of thymocytes. PTIP stably associates with complexes containing the chromatin methyltransferases MLL3 and MLL4, which modify chromatin in order to activate gene transcription. Here we demonstrate that PTIP contributes to Th17 differentiation and function via regulation of both c-Maf and AHR. Using CD4+ T cells from Ptipf/fCD4 Cre+ (PTIP−/−) mice and Cre- (WT) controls in a T cell transfer model of chronic colitis, we determined that RAG2−/− mice receiving WT cells had aggressive colitis with high expression of IL-17 in the intestine. However, in mice receiving PTIP−/− cells there was a reduction in IL-17 and an increase in IL-22 expression. The change in IL-17 and IL-22 expression in PTIP−/− mice was confirmed in vitro. Further analysis by chromatin immunoprecipitation (ChIP) assay showed that MLL3 binding and its dependent chromatin modifications at the loci for IL-17, c-Maf and AHR were enhanced in WT Th17 cells when compared to Th0 conditions and reduced in PTIP−/− Th17 cells. These data highlight, for the first time, that PTIP is essential for proper differentiation of Th17 cells.