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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adventitia / metabolism
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Adventitia / pathology
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Animals
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism*
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Antigen-Presenting Cells / physiology
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Aorta / immunology
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Aorta / metabolism
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Aorta / pathology
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Atherosclerosis / immunology
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Atherosclerosis / pathology*
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CD11 Antigens / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism*
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CD4-Positive T-Lymphocytes / physiology
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Cell Communication*
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Cell Movement
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Cell Proliferation
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Cell Tracking
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Cells, Cultured
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Coculture Techniques
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Cytokines / metabolism
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Dendritic Cells / physiology
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Diet, High-Fat
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Female
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Leukocyte Common Antigens / metabolism
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Lipoproteins, LDL / metabolism
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / physiology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Plaque, Atherosclerotic / pathology
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Tissue Culture Techniques
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Vasculitis / immunology
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Vasculitis / pathology*
Substances
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Apolipoproteins E
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CD11 Antigens
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Cytokines
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Lipoproteins, LDL
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oxidized low density lipoprotein
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Leukocyte Common Antigens
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Ptprc protein, mouse