RRC ID 47248
Author Matsumoto T, Sasaki N, Yamashita T, Emoto T, Kasahara K, Mizoguchi T, Hayashi T, Yodoi K, Kitano N, Saito T, Yamaguchi T, Hirata K.
Title Overexpression of Cytotoxic T-Lymphocyte-Associated Antigen-4 Prevents Atherosclerosis in Mice.
Journal Arterioscler Thromb Vasc Biol
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.
Volume 36(6)
Pages 1141-51
Published 2016-6-1
DOI 10.1161/ATVBAHA.115.306848
PII ATVBAHA.115.306848
PMID 27055906
MeSH Animals Aorta / immunology Aorta / metabolism* Aorta / pathology Aortic Diseases / genetics Aortic Diseases / immunology Aortic Diseases / metabolism Aortic Diseases / prevention & control* Apolipoproteins E / deficiency Apolipoproteins E / genetics Atherosclerosis / genetics Atherosclerosis / immunology Atherosclerosis / metabolism Atherosclerosis / prevention & control* B7-1 Antigen / metabolism B7-2 Antigen / metabolism CD11c Antigen / metabolism CD28 Antigens / metabolism CTLA-4 Antigen / genetics CTLA-4 Antigen / metabolism* Cell Proliferation Cells, Cultured Dendritic Cells / metabolism Female Genotype Lymphocyte Activation Macrophages / metabolism Male Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Phenotype Plaque, Atherosclerotic Signal Transduction T-Lymphocytes / immunology T-Lymphocytes / metabolism* Up-Regulation
IF 6.604
Times Cited 29
Mice RBRC00144