CXCR6 promotes atherosclerosis by supporting T-cell homing, interferon-γ production, and macrophage accumulation in the aortic wall

Background - T lymphocytes are thought to be important in atherosclerosis, but very little is known about the mechanisms of lymphocyte recruitment into atherosclerosis-prone aortas. In this study we tested the hypothesis that CXCR6, a chemokine receptor that is expressed on a subset of CD4(+) T helper I cells and natural killer T cells, is involved in lymphocyte homing into the aortic wall and modulates the development and progression of atherosclerosis. Methods and Results - To investigate the role of CXCR6 in the development and progression of atherosclerosis, we bred CXCR6-deficient (CXCR6(GFP/GFP)) mice with apolipoprotein E-deficient (ApoE(-/-)) mice. We found that CXCR6(GFP/GFP) ApoE(-/-) mice fed a Western diet for 17 weeks or a chow diet for 56 weeks had decreased atherosclerosis compared with ApoE(-/-) controls. Flow cytometry analysis of the aortas from CXCR6 (GFP/GFP)(3FP/ApoE(-/-) mice showed that the reduction of atherosclerosis was accompanied by a decreased percentage of CXCR6+ T cells within the aortas. Short-term homing experiments demonstrated that CXCR6 is involved in the recruitment of CXCR6(+) leukocytes into the atherosclerosis-prone aortic wall. The reduced percentage of CXCR6(+) T cells within the aortas resulted in significantly diminished production of interferon-gamma and reduction of CD11 b(+)/CD68(+) inacrophages in the aorta. Conclusions - These data provide evidence for a proatherosclerotic role of CXCR6. Absence of CXCR6 alters the recruitment of CXCR6(+) leukocytes and modulates the local immune response within the aortic wall.