A two-amino-acid substitution in the transcription factor RORγt disrupts its function in T H 17 differentiation but not in thymocyte development.

The transcription factor RORγt regulates differentiation of the TH 17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of RORγt prevents TH 17 cell-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in RORγt (RORγtM ) that 'preferentially' disrupted TH 17 differentiation but not thymocyte development. Mice expressing RORγtM were resistant to EAE associated with defective TH 17 differentiation but maintained normal thymocyte development and normal lymph-node genesis, except for Peyer's patches. RORγtM showed less ubiquitination at Lys69 that was selectively required for TH 17 differentiation but not T cell development. This study will inform the development of treatments that selectively target TH 17 cell-mediated autoimmunity but do not affect thymocyte development or induce lymphoma.