A two-amino-acid substitution in the transcription factor RORγgt disrupts its function in TH17 differentiation but not in thymocyte development

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