A two-amino-acid substitution in the transcription factor RORγt disrupts its function in T17 differentiation but not in thymocyte development.

The transcription factor RORγt regulates differentiation of the T17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of RORγt prevents T17 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 (RORγt) that 'preferentially' disrupted T17 differentiation but not thymocyte development. Mice expressing RORγt were resistant to EAE associated with defective T17 differentiation but maintained normal thymocyte development and normal lymph-node genesis, except for Peyer's patches. RORγt showed less ubiquitination at Lys69 that was selectively required for T17 differentiation but not T cell development. This study will inform the development of treatments that selectively target T17 cell-mediated autoimmunity but do not affect thymocyte development or induce lymphoma.