Selective disruption of RORγt-CBFβ interaction by IMU-935 prevents RORγt-dependent Th17 autoimmunity but not thymocyte development

RORγt is a key transcription factor regulating both Th17 differentiation and thymocyte development. Although Th17 cells drive autoimmune diseases, inhibiting RORγt to treat autoimmunity also disrupts thymocyte development and can cause lethal thymic lymphoma. We identified a previously unreported RORγt cofactor, CBFβ, and a highly selective RORγt inhibitor, IMU-935, that preferentially disrupt the RORγt-CBFβ interaction in Th17 cells but not thymocytes. This interaction is essential for RORγt function; mice with a RORγt mutant unable to bind CBFβ had impaired Th17 differentiation, were resistant to experimental autoimmune encephalomyelitis (EAE), and had defective thymocyte development. IMU-935 inhibited Th17 differentiation and reduced EAE severity without affecting thymocyte development by selectively targeting the RORγt-CBFβ interaction in Th17 cells but not in thymocytes. This differential effect arose because different concentrations of IMU-935 were required to disrupt the interaction in Th17 cells versus thymocytes, due to varying levels of RUNX1 that compete with RORγt for CBFβ binding. This study reveals an unreported mechanism for RORγt regulation and a selective RORγt inhibitor that prevents Th17-driven autoimmunity without the risk of lethal lymphoma from thymocyte disruption.