UCLA

RORγt is known to instruct the differentiation of T helper 17 (T_H17) 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_H17 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_H17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of T_H17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORγt to bind to and activate Runx1 expression critical for T_H17-mediated EAE. Thus, RORγt regulates the effector function of T_H17 cells in addition to T_H17 differentiation. This work informs the development of RORγt-based therapies that specifically target the effector function of T_H17 cells responsible for autoimmunity.