Tissue-Resident Memory T Cells in Rheumatoid Immune Diseases: Pathogenic Mechanisms and Therapeutic Strategies

Tissue-resident memory T (TRM) cells persist long-term in non-lymphoid tissues and provide rapid local immune protection, yet emerging evidence shows they also act as key drivers of chronic inflammation and relapse in rheumatoid immune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and primary Sjögren’s syndrome (pSS). A systematic search of PubMed, Web of Science, and Google Scholar (through October 2025) identified studies on TRM cell biology, pathogenic roles, and therapeutic modulation in autoimmune diseases. This review summarizes the fundamental features of TRM cells, including their TGF-β and IL-15 dependent development, tissue-specific heterogeneity, and unique metabolic programs. It highlights disease-specific pathogenic mechanisms: promotion of osteoclastogenesis and chronic synovial inflammation via Granulocyte-macrophage colony stimulating factor (GM-CSF) and the IL-23/IL-17 axis in RA; amplification of type I interferon responses and autoantibody production in SLE; potential contribution to fibrosis through TGF-β secretion in SSc; and mediation of glandular injury through cytotoxicity in pSS. Therapeutic strategies targeting TRM cells—such as JAK inhibitors, IL-17/IL-23 blockade, disruption of residency signals, metabolic interventions, and microenvironmental remodeling via nanotechnology—are critically evaluated. Challenges remain in achieving tissue-specific targeting without compromising systemic immune memory. Future directions include spatial transcriptomics, organoid models, and artificial intelligence to support precision medicine. Targeting TRM cells presents a promising novel avenue for achieving long-term remission and potentially even a cure for rheumatoid immune diseases.