The Functional Characterization of Invariant Natural Killer T Cells and the Chemokine Receptor CXCR6 in a Mouse Model of Inflammatory Arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and an influx of immune cells, leading to irreversible joint damage. The chemokine receptor CXCR6 is highly expressed on T lymphocytes isolated from the synovium of patients with inflammatory arthritis, and the chemokine CXCL16 is present at elevated levels in both soluble and transmembrane forms. This suggests that CXCR6 and CXCL16 regulate T cell activation or infiltration in arthritic joints. This study investigates the role of CXCR6 in arthritis development by examining its effects on T cell activation and infiltration into the arthritic joints in collagen-induced arthritis (CIA), an animal model of RA. Similar to the inflamed joints in arthritis patients, the numbers of CXCR6+ T cells were increased in the inflamed paws of arthritic mice. The incidence of arthritis and severity of disease were significantly reduced in CXCR6-deficient (CXCR6-/-) or CXCL16-/- mice compared to wild-type mice. T cells from CXCR6-/- mice exhibited reduced RANKL expression and impaired proinflammatory cytokine polarization, resulting in decreased IL-17A– and IFN-γ-producing cells. T cell accumulation within the arthritic paws was reduced in CXCR6-/- mice and homing of activated CXCR6-/- T cells to the inflamed paws was impaired compared to recruitment of wild-type T cells. Therefore, CXCR6-CXCL16 interactions play an important role in regulating effector T cell responses and represent promising therapeutic targets in inflammatory arthritis. Invariant natural killer T (iNKT) cells are an important immunoregulatory T cell subset that express high levels of CXCR6. Defects in iNKT cell populations in RA patients suggest they may play an important role in inflammatory arthritis. Invariant NKT cells were increased in the tissues of wild-type CIA mice, whereas iNKT cell-deficient Jα18-/- mice were resistant to disease development. Jα18-/- mice were reconstituted with iNKT cells from wild-type and gene targeted mice to examine the role of iNKT cell-derived proinflammatory cytokines in CIA. Adoptive transfer of wild-type iNKT cells, but not IFN-γ– or TNF-deficient iNKT cells, restored arthritis susceptibility in Jα18-/- mice. Therefore, iNKT cell-targeted treatment strategies that harness the immunoregulatory potential of iNKT cells may be of therapeutic benefit in RA.