Functional and dysfunctional T regulatory cell states in human tissues in RA and other autoimmune arthritic diseases

Regulatory T cells (T_reg cells), characterized by FOXP3 expression, maintain immune homeostasis, but their function is impaired in autoimmune diseases such as rheumatoid arthritis (RA). Here we used single-cell RNA sequencing to analyze T_reg cells in synovial tissues from patients with RA. We identified two predominant T_reg states, CD25^hiCXCR6^pos T_reg cells and dysfunctional CD25^loAREG^pos T_reg cells, both enriched in synovial tissues but not in blood. Cortisol, activated by fibroblasts, drove AREG expression and impaired suppressive function in CD25^loAREG^pos T_reg cells, and AREG promoted an inflammatory phenotype in synovial fibroblasts. By contrast, CD25^hiCXCR6^pos T_reg cells remained highly suppressive and were supported by membrane-bound tumor necrosis factor (TNF)-expressing macrophages. TNFR2 engagement prevented or reversed the dysfunctional T_reg cell state. These two T_reg cell subsets were also observed in juvenile idiopathic arthritis, indicating shared mechanisms across inflammatory arthritis. These findings define distinct pathways driving functional and dysfunctional T_reg cell states in inflamed tissues and implicate potential therapeutic strategies.