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 RORγt (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 exacerbate diseases after dextran sulfate sodium (DSS) induced colitis and experimental autoimmune encephalomyelitis (EAE) challenge. Together, these results highlight the essential role of RORγtS182 in resolving T cell-mediated tissue inflammation, providing a potential therapeutic target to combat autoimmune diseases.
Graphical AbstractSerine 182 on RORγt limits T cell mediated intestine and central nervous system inflammation.
Highlights
Single-cell RNA-seq of the colonic lamina propria reveals CD4+ T cell heterogeneity under steady state and during dextran sulfate induced colitis.
The master transcription factor RORγt of Th17 and Treg cell functions is phosphorylated at serine 182.
Serine 182 on RORγt represses IL-1β-induced IL-17A production in in Th17 cells and potentiates IL-10 production in colonic LT-like Treg cells.
Phospho-null RORγtS182A mice succumb to exacerbate inflammation when challenged in models of colitis and experimental autoimmune encephalomyelitis.
Competing Interest Statement
The authors have declared no competing interest.