Regulation of Cytokine Polarization and T Cell Recruitment to Inflamed Paws in Mouse Collagen-Induced Arthritis by the Chemokine Receptor CXCR6
The chemokine receptor CXCR6 is highly expressed on lymphocytes isolated from the synovium of patients with rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis, suggesting that CXCR6 regulates immune cell activation or infiltration into arthritic joints. This study was undertaken to examine the role of CXCR6 in T cell activation and arthritis development.
A collagen-induced arthritis model was used to examine arthritis development in wild-type and CXCR6−/− mice. CXCR6 expression, lymphocyte accumulation, and intracellular cytokine production were examined by flow cytometry. Collagen-specific antibodies were measured in the serum. Collagen-specific recall responses were examined in vitro via proliferation and cytokine release assays. T cell homing to inflamed joints was examined using competitive adoptive transfer of dye-labeled lymphocytes from wild-type and CXCR6−/− mice.
The numbers of CXCR6+ T cells were increased in the paws and draining lymph nodes of arthritic mice. The incidence of arthritis, disease severity, extent of T cell accumulation, and levels of collagen-specific IgG2a antibodies were significantly reduced in CXCR6−/− mice compared to wild-type mice. T cells from wild-type mice exhibited Th1 (interferon-γ [IFNγ]) polarization in the inguinal lymph nodes following immunization. At disease peak, this shifted to a Th17 (interleukin-17A [IL-17A]) response in the popliteal lymph nodes. T cells in CXCR6−/− mice exhibited impaired cytokine polarization, resulting in a decreased frequency and number of IL-17A– and IFNγ-producing cells. Recruitment of activated CXCR6−/− mouse T cells to the inflamed paws was impaired compared to recruitment of wild-type mouse T cells.
These experiments demonstrate that CXCR6 plays important roles in the pathogenesis of arthritis through its effects on both T cell cytokine polarization and homing of T cells to inflamed joints.