title: Overexpression of Cytotoxic T-Lymphocyte-Associated Antigen-4 Prevents Atherosclerosis in Mice.
abstract: 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.
  
  
  
  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.
  
  
  
  CTLA-4 regulates atherosclerosis by suppressing proatherogenic immune responses and could be an attractive therapeutic target for atherosclerosis.
authors.affiliation: 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.).
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: 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.
authors.forename: Naoto
authors.initials: N
authors.lastname: Sasaki
authors.affiliation: 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.).
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: 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.).
authors.forename: Takuo
authors.initials: T
authors.lastname: Emoto
authors.affiliation: 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.).
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: 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.).
authors.forename: Taiji
authors.initials: T
authors.lastname: Mizoguchi
authors.affiliation: 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.).
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: 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.).
authors.forename: Keiko
authors.initials: K
authors.lastname: Yodoi
authors.affiliation: 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.).
authors.forename: Naoki
authors.initials: N
authors.lastname: Kitano
authors.affiliation: 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.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: 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.).
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: 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.).
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hirata
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D005838:Genotype; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001057:Apolipoproteins E; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D039521:CD11c Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse
keywords: T-lymphocytes; atherosclerosis; dendritic cells; immune system; inflammation