Zhang Xueyou, Cao Mingde, Fu Bruma Sai-Chuen, Wang Jian-Quan, Ong Michael Tim-Yun, Yung Patrick Shu-Hang
Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Center for Neuromusculoskeletal Restorative Medicine (CNRM), The Chinese University of Hong Kong, Hong Kong, China.
Department of Sports Medicine, Peking University Third Hospital, Institute of Sports Medicine of Peking University, Beijing, China; Beijing Key Laboratory of Sports Injuries, Beijing, China; Engineering Research Centre of Sports Trauma Treatment Technology and Devices, Ministry of Education, Beijing, China.
Pharmacol Res. 2025 Dec;222:108041. doi: 10.1016/j.phrs.2025.108041. Epub 2025 Nov 19.
Osteoarthritis (OA) affects over 500 million individuals globally and currently lacks effective disease-modifying therapies. Although chronic synovial inflammation is recognized as a central driver of joint damage, clinical trials targeting IL-1β, TNF, and related inflammatory pathways have shown limited benefit, suggesting that immune dysregulation in OA extends beyond innate mechanisms. Emerging evidence highlights a role for adaptive immunity, particularly regulatory T (T) cells, as potential targets for immunomodulation. This review critically examines the contribution of adaptive immune responses to OA, emphasizing synovial T cells and their therapeutic potential. Clinical, experimental, and genetic studies consistently reveal infiltration of antigen-experienced T and B lymphocytes, evidence of clonal expansion, autoantibody generation, and robust local antigen-presenting activity in OA joints. Synovial T cells are detectable throughout the disease course, exhibiting tissue-resident and activated phenotypes. Clinical observations and Mendelian randomization analyses further indicate a protective role for CD25⁺ T cells. However, critical questions remain regarding their functional stability, antigen specificity, and immunoregulatory capabilities within OA joints. Insights from other inflammatory diseases point to several mechanistic avenues through which T cells could mediate therapeutic benefit, offering substantial yet untested opportunities for translation into the OA context. In conclusion, accumulating evidence underscores a significant role for sustained adaptive immune activity in OA pathogenesis. Despite the consistent presence of synovial T cells, their precise immunological functions remain unresolved. Defining the antigen specificity, suppressive capacity, and functional stability of these cells is essential for evaluating their therapeutic potential as targets for innovative immune-based disease-modifying strategies in OA.
