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

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

Abstract

The transcription factor RORγt regulates differentiation of the TH17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of RORγt prevents TH17 cell-mediated experimental autoimmune encephalomyelitis (EAE), it also disruptsthymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in RORγt (RORγtM) that ‘preferentially’ disrupted TH17 differentiation but not thymocyte development. Mice expressing RORγtM were resistant to EAE associated with defective TH17 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 TH17 differentiation but not T cell development. This study will inform the development of treatments that selectively target TH17 cell-mediated autoimmunity but do not affect thymocytedevelopment or induce lymphoma.

Authors: He Z1, Ma J1, Wang R1,2, Zhang J1,2, Huang Z3, Wang F1, Sen S1, Rothenberg EV4, Sun Z1.

Influence Factor: 21.506

Citation: Nat Immunol 18, 1128-1138 (2017).

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