@article{8b9102f3f122487d88b33237302dad5e,
title = "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.",
author = "Xiancai Zhong and Hongmin Wu and Wencan Zhang and Yousang Gwack and Weirong Shang and Lee, {Kyle O.} and Noah Isakov and Zhiheng He and Zuoming Sun",
note = "Funding Information: We thank J. C. Zuniga-Pflucker (University of Toronto) for the DP9-DL4 stroma cell line, W.S. Pear (University of Pennsylvania) for the retroviral vector MIGR1, I. Taniuchi for the MSCV-Runx1 retroviral vector, Y.C. Yuan (Bioinformatics Core of City of Hope) for the guidance of Partek Flow, and Biocytogen for assisting with the design and generation of RORγtK256R/K256R mice. We also thank the following City of Hope core services: Animal Resource Center, Integrative Genomics Core, Flow Cytometer Core, Mass Spectrometry Core, and Bioinformatics Core. We thank C. S. Jayasena for reviewing and editing the manuscript. This work was supported by grants from NIH R01-AI109644, R21-AI163256, institutional pilot funding, Jackie and Bruce Barrow Cancer Research Scholars{\textquoteright} Program, and Caltech-CoH Biomedical Initiative. The research reported in this publication included work performed in the animal, genomic, flow cytometry, and mass spectrometry cores supported under NIH grant P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.",
year = "2022",
month = oct,
day = "21",
doi = "10.1126/sciadv.adc9221",
language = "English",
volume = "8",
pages = "eadc9221",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "42",
}