Tissue-resident memory T cells in autoimmune chronicity and relapse: mechanisms and therapeutic implications

Tissue-resident memory T (Trm) cells are a specialized subset of memory T cells that persist in peripheral tissues (skin, joints, intestine) without recirculating, serving as a frontline defense against pathogen reinfection. This protective function is exemplified by interleukin-15 (IL-15), C-X-C chemokine receptor type 6, and inducible T-cell co-stimulator signaling that are essential for Trm-mediated immunity against viruses and bacteria. However, the same long-lived persistence becomes detrimental in autoimmunity. Activated autoreactive Trm cells accumulate in lesions of psoriasis, rheumatoid arthritis, inflammatory bowel disease, vitiligo, and other conditions. Upon activation by autoantigens or inflammatory cues, they settle in tissues, continuously produce pro-inflammatory cytokines (interferon-gamma, tumor necrosis factor-alpha, IL-17), directly mediate tissue damage, and recruit other immune cells, thereby amplifying chronic inflammation. Their persistence drives disease relapse, lesion chronicity, and tissue-specific confinement. Thus, Trm cells embody a double-edged sword-essential for local immune protection but also important connectors linking autoimmune initiation to chronic pathology maintenance. In this review, we summarized recent advances in Trm cell biology and examined their growing implications in the pathogenesis of autoimmune diseases. We further discuss the molecular and cellular mechanisms through which Trm cells drive organ-specific, chronic inflammatory responses, underscoring their role across diverse autoimmune disorders. Hopefully, the emerging therapeutic strategies aiming at modulating Trm cell generation, persistence, and function will highlight both the promise and obstacles in translating these approaches into clinical practice.