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 hi CXCR6 pos T reg cells and dysfunctional CD25 lo AREG 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 lo AREG pos T reg cells, and AREG promoted an inflammatory phenotype in synovial fibroblasts.
By contrast, CD25 hi CXCR6 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.
Nature Immunology published a clinical update in Infectious Disease on 16 Jun 2026.
The item focuses on Functional and dysfunctional T regulatory cell states in human tissues in RA and other autoimmune arthritic diseases.
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