Takuya Matsumoto1, Naoto Sasaki2, Tomoya Yamashita1, Takuo Emoto1, Kazuyuki Kasahara1, Taiji Mizoguchi1, Tomohiro Hayashi1, Keiko Yodoi1, Naoki Kitano1, Takashi Saito1, Tomoyuki Yamaguchi1, Ken-Ichi Hirata1. 1. From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (T.M., N.S., T.Y., T.E., K.K., T.M., T.H., K.Y., N.K., K.-i.H.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan (T.S.); and Laboratory for Cell Signaling (T.S.) and Department of Single Molecule Imaging, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.Y.). 2. From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (T.M., N.S., T.Y., T.E., K.K., T.M., T.H., K.Y., N.K., K.-i.H.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan (T.S.); and Laboratory for Cell Signaling (T.S.) and Department of Single Molecule Imaging, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.Y.). sasakin@med.kobe-u.ac.jp.
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.
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.
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