Adaptive immunity in osteoarthritis: Mechanisms and opportunities for regulatory T-cell-targeted therapy

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_reg) cells, as potential targets for immunomodulation. This review critically examines the contribution of adaptive immune responses to OA, emphasizing synovial T_reg 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_reg 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_reg 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_reg 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_reg 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.