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

Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1141-51. doi: 10.1161/ATVBAHA.115.306848. Epub 2016 Apr 7.

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.

Keywords: T-lymphocytes; atherosclerosis; dendritic cells; immune system; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Apolipoproteins E
  • B7-1 Antigen
  • B7-2 Antigen
  • CD11c Antigen
  • CD28 Antigens
  • CTLA-4 Antigen
  • Cd86 protein, mouse
  • Ctla4 protein, mouse