Abstract
Abstract RORgt regulates Th17 differentiation, thymic T cell development, and lymph node genesis. Although elimination of RORgt prevents Th17-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, eventually leading to lethal thymic lymphoma. To specifically targeting RORgt-dependent Th17 autoimmunity, it is thus essential to distinguish between RORgt-regulated mechanisms in Th17 differentiation and thymocyte development. We identified two amino acid mutations within the hinge region of RORgt (RORgtM) that preferentially disrupted Th17 differentiation but not thymocyte development. Mice expressing RORgtM were resistant to Th17-mediated autoimmune EAE that was associated with defective Th17 differentiation, but maintained normal thymic T cell development and lymph node genesis, except for Peyer’s patches. The RORgtM mouse is thus an effective model for specifically evaluating RORgt-dependent Th17 immunity. We further showed that RORgtM ubiquitination at lysine 69 (K69) was greatly reduced. Mutation of wild-type RORgt K69 to arginine to prevent ubiquitination preferentially impaired Th17 differentiation but not T cell development, similar to RORgtM. Therefore, our study distinguished between important RORgt-regulated functions via a critical ubiquitination event. This study will inform the development of RORgt-based treatments that selectively target Th17-mediated autoimmunity without interrupting the development of T cells and peripheral lymphoid organs.
Published Version
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