Decoupling the role of RORγt in the differentiation and effector function of T<sub>H</sub>17 cells.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36269826.
- Also identified by DOI 10.1126/sciadv.adc9221 and PMC identifier 9586477.
- Licence recorded as CC BY-NC.
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Abstract
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-dependent thymocyte development, and T<sub>H</sub>17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of T<sub>H</sub>17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORγt to bind to and activate <i>Runx1</i> expression critical for T<sub>H</sub>17-mediated EAE. Thus, RORγt regulates the effector function of T<sub>H</sub>17 cells in addition to T<sub>H</sub>17 differentiation. This work informs the development of RORγt-based therapies that specifically target the effector function of T<sub>H</sub>17 cells responsible for autoimmunity.