Overexpression of Cytotoxic T-Lymphocyte–Associated Antigen-4 Prevents Atherosclerosis in Mice. Issue 6 (June 2016)

• Record Type: Journal Article
• Authors: Matsumoto, Takuya; Sasaki, Naoto; Yamashita, Tomoya; Emoto, Takuo; Kasahara, Kazuyuki; Mizoguchi, Taiji; Hayashi, Tomohiro; Yodoi, Keiko; Kitano, Naoki; Saito, Takashi; Yamaguchi, Tomoyuki; Hirata, Ken-ichi
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 36:Issue 6(2016)
• Publication Date: 2016-06
• Subjects: atherosclerosis -- dendritic cells -- immune system -- inflammation -- T-lymphocytes; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.115.306848
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : 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. Abstract : Supplemental Digital Content is available in the text.