Tissue-resident memory T cells: The key frontier in local synovitis memory of rheumatoid arthritis

Rheumatoid arthritis (RA) is a highly disabling, systemic autoimmune disease. It presents a remarkable tendency to recur, which renders it almost impossible for patients to live without drugs. Under such circumstances, many patients have to suffer the pain of recurrent attacks as well as the side effects of long-term medication. Current therapies for RA are primarily systemic treatments without targeting the problem that RA is more likely to recur locally. Emerging studies suggest the existence of a mechanism mediating local memory during RA, which is closely related to the persistent residence of tissue-resident memory T cells (T_RM). T_RM, one of the memory T cell subsets, reside in tissues providing immediate immune protection but driving recurrent local inflammation on the other hand. The heterogeneity among synovial T_RM is unclear, with the dominated CD8⁺ T_RM observed in inflamed synovium of RA patients coming into focus. Besides local arthritis relapse, T_RM may also contribute to extra-articular organ involvement in RA due to their migration potential. Future integration of single-cell RNA sequencing (scRNA-seq) with spatial transcriptomics to explore the gene expression patterns of T_RM in both temporal dimension and spatial dimension may help us identify specific therapeutic targets. Targeting synovial T_RM to suppress local arthritis flares while using systemic therapies to prevent extra-articular organ involvement may provide a new perspective to address RA recurrence.