Arthritis flares mediated by tissue-resident memory T cells in the joint

Rheumatoid arthritis is a systemic disease, flares typically occur in a subset of joints that is distinctive for each patient. Pursuing this intriguing pattern, we show that arthritis recurrence is mediated by long-lived synovial resident memory T cells (T-RM). In three murine models, CD8+ cells bearing T-RM markers remain in previously inflamed joints during remission. These cells are bona fide T-RM, exhibiting failure to migrate from joint to joint, preferential uptake of fatty acids, and long-term residency. Disease flares result from T-RM activation by antigen, leading to CCL5-mediated recruitment of circulating effector cells. Correspondingly, T-RM depletion ameliorates recurrence in a site-specific manner. Human rheumatoid arthritis joint tissues contain a comparable CD8+-predominant T-RM population, most evident in late-stage non-inflamed synovium, exhibiting limited T cell receptor diversity and a pro-inflammatory transcriptomic signature. Together, these findings establish synovial T-RM cells as a targetable mediator of disease chronicity in autoimmune arthritis