Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis
Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis
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DOI：
10.1172/jci61758
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发表时间：
2012-09-01
影响因子：
15.9
通讯作者：
Ley, Klaus
中科院分区：
文献类型：
--
作者：
Koltsova, Ekaterina K.;Garcia, Zacarias;Ley, Klaus
动脉粥样硬化是一种大中型动脉的慢性炎症性疾病，其特征是白细胞在血管壁中积聚。先天性和适应性免疫反应都有助于动脉粥样硬化的形成，但动脉粥样硬化相关抗原的身份和抗原呈递在这种疾病中的作用仍然很差。我们开发了动脉粥样硬化小鼠的活细胞成像，以比较正常和动脉粥样硬化小鼠中APC的行为和作用。我们发现，CD 4（+）T细胞能够与荧光标记的（CD 11 c-YFP+）APC在主动脉壁的同源抗原的存在下，但不是不存在，相互作用。在动脉粥样硬化倾向的Apoe（-/-）CD 11 c-YFP+小鼠中，APC与主动脉中的CD 4（+）T细胞广泛相互作用，导致细胞活化和增殖以及IFN-γ和TNF-α的分泌。这些细胞因子增强了巨噬细胞对氧化和最低限度修饰的LDL的摄取。我们的结论是，抗原呈递细胞的CD 4（+）T细胞在动脉壁引起局部T细胞活化和促炎细胞因子的生产，促进动脉粥样硬化通过维持慢性炎症和诱导泡沫细胞形成。
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-gamma and TNF-alpha. 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.