Regulation of Pathogenic T Helper 17 Cell Differentiation by Steroid Receptor Coactivator-3

T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor ROR gamma t, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here, we show that steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of experimental autoimmune encephalitis (EAE) associated with decreased Th17 cell generation in vivo was observed in mice with SRC-3 deletion specifically in T cells. In vitro, SRC-3 deficiency did not affect TGF-beta/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarray analysis revealed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il 17a and Mil loci in a ROR gamma t-dependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical for ROR gamma t-dependent gene expression in Th17 cell-driven autoimmune diseases.