Regulation of pathogenic T helper 17 cell differentiation by steroid receptor coactivator-3. 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 RORgt, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here we show that the 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-/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarrays were used to showed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il17a and Il1r1 loci in a RORtdependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical in RORt-dependent gene expression during Th17 cell-driven autoimmune diseases. Overall design: Both WT and SRC-3 deficient naive CD4+ T cells were stimulated with anti-CD3 and anti-CD28 antibodies in the absence of exogenous cytokines (Th 0 cells), or differentiated with IL-1, IL-6 plus IL-23 (pathogenic Th17 cells).