Mechanical loading of joint modulates T cells in lymph nodes to regulate osteoarthritis

Abstract

ObjectiveThe crosstalk of joint pathology with local lymph nodes in osteoarthritis (OA) is poorly understood. We characterized the change in T cells in lymph nodes following load-induced OA and established the association of the presence and migration of T cells to the onset and progression of OA. MethodsWe used an in vivo model of OA to induce mechanical load-induced joint damage. After cyclic tibial compression of mice, we analyzed lymph nodes for T cells using flow cytometry and joint pathology using histology and microcomputed tomography. The role of T-cell migration and presence of T-cell type was examined using TCRα-/- and an immunomodulatory drug, Sphingosine-1-phosphate (S1P) receptor inhibitor-treated mice, respectively. ResultsWe demonstrate a significant increase in T-cell populations in local lymph nodes in response to joint injury in 10, 16, and 26-week-old mice, and as a function of load duration, 1, 2, and 6 weeks. T-cell expression of inflammatory cytokine markers increased in the local lymph nodes and was associated with load-induced OA progression in the mouse knee. Joint loading in TCRα-/- mice reduced both cartilage degeneration (OARSI: TCRα 0.568, 0.981-0.329 CI; WT 1.328, 2.353-0.749 CI) and osteophyte formation. Inhibition of T-cell egress from lymph nodes attenuated load-induced cartilage degradation (OARSI: Fingolimod: 0.509, 1.821-0.142 CI; Saline 1.210, 1.932-0.758 CI) and decreased localization of T cells in the synovium. ConclusionsThese results establish the association of lymph node-resident T cells in joint damage and suggest that the S1P receptor modulators and T-cell immunotherapies could be used to treat OA.