Decoupling the role of RORγt in the differentiation and effector function of T(H)17 cells

RORγt is known to instruct the differentiation of T helper 17 (T(H)17) cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORγt plays a distinct role in the differentiation and effector function of T(H)17 cells. Here, we show that mutation of RORγt lysine-256, a ubiquitination site, to arginine (K256R) separates the RORγt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORγt-dependent thymocyte development, and T(H)17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of T(H)17 cell–mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORγt to bind to and activate Runx1 expression critical for T(H)17-mediated EAE. Thus, RORγt regulates the effector function of T(H)17 cells in addition to T(H)17 differentiation. This work informs the development of RORγt-based therapies that specifically target the effector function of T(H)17 cells responsible for autoimmunity.