Overexpression of Cytotoxic T-Lymphocyte–Associated Antigen-4 Prevents Atherosclerosis in Mice

Objective— Although T-cell–mediated chronic inflammation contributes to atherosclerosis development, the role of a negative regulatory molecule cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) in atherosclerosis is poorly understood. We investigated the effects of CTLA-4 overexpression on atherosclerosis in apolipoprotein E–deficient (Apoe −/− ) mice.Approach and Results— We generated CTLA-4 transgenic (CTLA-4-Tg)/Apoe −/− mice that display constitutive cell surface and intracellular expression of CTLA-4 in T cells and assessed atherosclerosis at age 16 weeks. CTLA-4 overexpression significantly reduced atherosclerotic lesion formation and intraplaque accumulation of macrophage and CD4+ T cells in the aortic root compared with controls. CTLA-4-Tg/Apoe −/− mice showed decreased numbers of effector CD4+ T cells and decreased expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, and a costimulatory molecule CD28, on CD11c+ dendritic cells compared with controls. Consistent with in vivo findings, in vitro experiments revealed that CD4+ T cells from CTLA-4-Tg/Apoe −/− mice showed decreased proliferative capacity and proinflammatory cytokine production, downregulated CD80 expression on CD11c+ dendritic cells, and suppressed the proliferation of other T cells by limiting the costimulatory pathway. Moreover, CD11c+ dendritic cells from CTLA-4-Tg/Apoe −/− mice showed reduced proliferative activity of T cells in vitro, suggesting the suppression of dendritic cell maturation in vivo.Conclusions— CTLA-4 regulates atherosclerosis by suppressing proatherogenic immune responses and could be an attractive therapeutic target for atherosclerosis.