Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis

J Clin Invest. 2012 Sep;122(9):3114-26. doi: 10.1172/JCI61758. Epub 2012 Aug 13.

Abstract

Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries characterized by leukocyte accumulation in the vessel wall. Both innate and adaptive immune responses contribute to atherogenesis, but the identity of atherosclerosis-relevant antigens and the role of antigen presentation in this disease remain poorly characterized. We developed live-cell imaging of explanted aortas to compare the behavior and role of APCs in normal and atherosclerotic mice. We found that CD4+ T cells were capable of interacting with fluorescently labeled (CD11c-YFP+) APCs in the aortic wall in the presence, but not the absence, of cognate antigen. In atherosclerosis-prone Apoe-/-CD11c-YFP+ mice, APCs extensively interacted with CD4+ T cells in the aorta, leading to cell activation and proliferation as well as secretion of IFN-γ and TNF-α. These cytokines enhanced uptake of oxidized and minimally modified LDL by macrophages. We conclude that antigen presentation by APCs to CD4+ T cells in the arterial wall causes local T cell activation and production of proinflammatory cytokines, which promote atherosclerosis by maintaining chronic inflammation and inducing foam cell formation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adventitia / metabolism
  • Adventitia / pathology
  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism*
  • Antigen-Presenting Cells / physiology
  • Aorta / immunology
  • Aorta / metabolism
  • Aorta / pathology
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / immunology
  • Atherosclerosis / pathology*
  • CD11 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / physiology
  • Cell Communication*
  • Cell Movement
  • Cell Proliferation
  • Cell Tracking
  • Cells, Cultured
  • Coculture Techniques
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / physiology
  • Diet, High-Fat
  • Female
  • Leukocyte Common Antigens / metabolism
  • Lipoproteins, LDL / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plaque, Atherosclerotic / pathology
  • Tissue Culture Techniques
  • Vasculitis / immunology
  • Vasculitis / pathology*

Substances

  • Apolipoproteins E
  • CD11 Antigens
  • Cytokines
  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • Leukocyte Common Antigens
  • Ptprc protein, mouse