Early synovial regulatory T cell engagement in posttraumatic osteoarthritis.

Abstract

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. 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. 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. 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.