Chemokine receptor 7 knockout attenuates atherosclerotic plaque development.

Abstract

Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the transition from innate to adaptive immune activation by coordinating the migration to and positioning of antigen-presenting dendritic cells and T cells in secondary lymphoid organs. More recently, it was shown that CCR7 is also responsible for T-cell migration into inflamed tissues and T-cell egress from these tissues via the afferent lymph. Thus, we investigated the influence of a systemic CCR7 deficiency on atherogenesis in atherosclerosis-prone low-density lipoprotein receptor (ldlr) knockout mice. CCR7 deficiency resulted in reduced atherosclerotic plaque development. CCR7(-/-) T cells showed impaired entry and exit behavior from atherosclerotic lesions. Oxidized low-density lipoprotein, a key molecule for atherogenesis with antigenic features, was used to pulse dendritic cells and to expand T cells ex vivo. Adoptive transfer of C57BL/6 wild-type T cells but not ccr7(-/-)-derived T cells primed with oxidized low-density lipoprotein-pulsed dendritic cells resulted in a reconstitution of atherogenesis in ccr7(-/-)/ldlr(-/-) mice. These results demonstrate that both CCR7-dependent T-cell priming in secondary lymphoid organs and CCR7-dependent recirculation of T cells between secondary lymphoid organs and inflamed tissue are crucially involved in atherosclerotic plaque development.