Early synovial regulatory T cell engagement in posttraumatic osteoarthritis

Objective Posttraumatic osteoarthritis (PTOA) develops despite restoration of joint biomechanics, suggesting that early post‐injury biological processes within the synovium shape disease trajectories. We investigated whether synovial regulatory T (T reg ) cells are engaged during the early phase following joint injury and whether experimental enrichment of this compartment is associated with altered local inflammation and PTOA‐related pathology. Methods Using surgically induced destabilization of the medial meniscus (DMM) and a non‐invasive anterior cruciate ligament (ACL) rupture model in mice, we characterized temporal dynamics and phenotypes of synovial T reg cells by high‐parameter flow cytometry and integrative single‐cell transcriptomic analysis. T reg cells were preferentially expanded using systemic low‐dose IL‐2/anti–IL‐2 complexes or intraarticular adeno‐associated virus–mediated IL‐2 delivery. Synovial inflammation, cartilage degeneration, and gait function were assessed. Results Synovial T reg cells accumulated rapidly after joint injury in both models, acquired activation‐ and tissue‐adaptation‐associated phenotypes distinct from lymphoid T reg populations, and were associated with local immune‐compositional changes. Experimental IL‐2–mediated enrichment of the synovial T reg compartment was accompanied by reduced synovitis, attenuated cartilage pathology, and partial improvement in load‐bearing gait parameters. Conclusion Early synovial T reg engagement represents a candidate joint‐localized immunoregulatory feature of PTOA initiation. Experimental enrichment of this compartment was associated with attenuated PTOA‐related features, supporting further investigation of T reg ‐specific mechanisms and precisely timed, joint‐localized immune modulation.