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

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