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Decoupling the role of RORγt in the differentiation and effector function of TH17 cells.


ABSTRACT: RORγt is known to instruct the differentiation of T helper 17 (TH17) cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORγt plays a distinct role in the differentiation and effector function of TH17 cells. Here, we show that mutation of RORγt lysine-256, a ubiquitination site, to arginine (K256R) separates the RORγt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORγt-dependent thymocyte development, and TH17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of TH17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORγt to bind to and activate Runx1 expression critical for TH17-mediated EAE. Thus, RORγt regulates the effector function of TH17 cells in addition to TH17 differentiation. This work informs the development of RORγt-based therapies that specifically target the effector function of TH17 cells responsible for autoimmunity.

SUBMITTER: Zhong X 

PROVIDER: S-EPMC9586477 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Decoupling the role of RORγt in the differentiation and effector function of T<sub>H</sub>17 cells.

Zhong Xiancai X   Wu Hongmin H   Zhang Wencan W   Gwack Yousang Y   Shang Weirong W   Lee Kyle O KO   Isakov Noah N   He Zhiheng Z   Sun Zuoming Z  

Science advances 20221021 42


RORγt is known to instruct the differentiation of T helper 17 (T<sub>H</sub>17) cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORγt plays a distinct role in the differentiation and effector function of T<sub>H</sub>17 cells. Here, we show that mutation of RORγt lysine-256, a ubiquitination site, to arginine (K256R) separates the RORγt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORγt-de  ...[more]

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