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 pattern 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 (TRM). In three murine models, CD8+ cells bearing TRM markers remain in previously inflamed joints during remission. These cells are bona fide TRM, exhibiting failure to migrate from joint to joint, preferential uptake of fatty acids, and long-term residency. Disease flares result from TRM activation by antigen, leading to CCL5-mediated recruitment of circulating effector cells. Correspondingly, TRM depletion ameliorates recurrence in a site-specific manner. Human rheumatoid arthritis joint tissues contain a comparable CD8+-predominant TRM population, 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 TRM cells as a targetable mediator of disease chronicity in autoimmune arthritis.

类风湿性关节炎是一种系统性自身免疫性疾病，然而疾病发作通常仅影响关节的特定子集，且这种分布模式对每位患者而言具有独特性。循着这一引人入胜的模式，本研究揭示关节炎的复发是由长寿的滑膜定居记忆T细胞（TRM）介导的。在三种小鼠模型中，带有TRM标志的CD8+细胞在缓解期仍停留在先前炎症的关节中。这些细胞是真正的TRM，表现出无法从关节迁移至关节，偏好摄取脂肪酸以及长期定居的特点。疾病的发作源于由抗原激活的TRM，导致CCL5介导的循环效应细胞的募集。相应地，通过特异性消除TRM可以改善疾病的复发。在人类类风湿性关节炎的关节组织中，存在一个与CD8+为主的TRM人群，这在晚期白细胞贫乏的滑膜中尤为明显，显示出有限的T细胞受体多样性和促炎转录组特征。综上所述，这些发现将滑膜TRM细胞确立为自身免疫性关节炎疾病慢性化的可靶向介质。