SRC3 Is a Cofactor for RORγt in Th17 Differentiation but Not Thymocyte Development

SRC3, a highly conserved member of the steroid receptor coactivator (SRC) family, is recruited by transcription factors to regulate cellular function. Previously, we demonstrated that SRC1, another highly conserved member of the SRC family, interacts with ROR gamma t to regulate Th17 differentiation. However, the relationship between SRC1 and SRC3 in the regulation of Th17 cell function remains unknown. In this study, we demonstrate that mouse SRC3 interacts with ROR gamma t in Th17 cells but not in thymocytes. In addition, Src3(-/-) mice exhibited defective Th17 differentiation and induction of experimental autoimmune encephalomyelitis but normal thymocyte development. Furthermore, a K313 to arginine mutation of ROR gamma t (ROR gamma t-K313R), which disrupts the interaction of ROR gamma t with SRC3 but not with SRC1, impairs Th17 differentiation but not thymocyte development. These data suggest that SRC3 works with SRC1 to regulate ROR gamma t-dependent Th17 differentiation but is not essential for ROR gamma t-dependent thymocyte development.