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

Xiancai Zhong, Hongmin Wu, Wencan Zhang, Yousang Gwack, Weirong Shang, Kyle O. Lee, Noah Isakov, Zhiheng He, Zuoming Sun

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Article numbereadc9221
Pages (from-to)eadc9221
JournalScience advances
Volume8
Issue number42
DOIs
StatePublished - 21 Oct 2022

ASJC Scopus subject areas

  • General

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