RORγt serine 182 tightly regulates T cell heterogeneity to maintain mucosal homeostasis and restrict tissue inflammation

Abstract

Unresolved inflammation causes tissue damage and contributes to autoimmune conditions. However, the molecules and mechanisms controlling T cell mediated inflammation remain to be fully elucidated. Here, we report an unexpected role of the RAR-Related Orphan Receptor-gamma protein (RORγt) in resolving tissue inflammation. Single-cell RNA-seq (scRNA-seq) revealed that an evolutionarily conserved serine 182 residue on ROR&γt (RORγtS182) is critical for restricting IL-1β-mediated Th17 activities and promoting anti-inflammatory cytokine IL-10 production in RORγt+ Treg cells in inflamed tissues. Phospho-null RORγtS182A knock-in mice experienced delayed recovery and succumbed to exacerbated diseases after dextran sulfate sodium (DSS) induced colitis and experimental autoimmune encephalomyelitis (EAE) challenge. Together, these results highlight the essential role of ROR&γtS182 in resolving T cell mediated tissue inflammation, providing a potential therapeutic target to combat autoimmune diseases.