Dynamic T cell–APC interactions sustain chronic inflammation in atherosclerosis
Ekaterina K. Koltsova, Zacarias Garcia, Grzegorz Chodaczek, Michael Landau, Sara McArdle, Spencer R. Scott, Sibylle von Vietinghoff, Elena Galkina, Yury I. Miller, Scott T. Acton, Klaus Ley
Ekaterina K. Koltsova, Zacarias Garcia, Grzegorz Chodaczek, Michael Landau, Sara McArdle, Spencer R. Scott, Sibylle von Vietinghoff, Elena Galkina, Yury I. Miller, Scott T. Acton, Klaus Ley
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Research Article Cardiology

Dynamic T cell–APC interactions sustain chronic inflammation in atherosclerosis

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.

Authors

Ekaterina K. Koltsova, Zacarias Garcia, Grzegorz Chodaczek, Michael Landau, Sara McArdle, Spencer R. Scott, Sibylle von Vietinghoff, Elena Galkina, Yury I. Miller, Scott T. Acton, Klaus Ley

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Figure 4

2-photon imaging of Apoe–/– CD4+ T cell–APC interaction in the plaque and adventitia of Apoe–/– aorta.

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2-photon imaging of Apoe–/– CD4+ T cell–APC interaction in the plaque an...
(A) Cross-sectional view of innominate artery plaque and media. CD11c-YFP+ cells are stained green, and SNARF-labeled Apoe–/– CD4+ T cells are stained red. (B) Velocities of individual freely migrating (n = 126) and interacting (n = 47) T cells. No exogenous antigen was added. Average is indicated by horizontal line. (C) Percent interaction with CD11c-YFP+CD4+ T cells isolated from spleens and lymph nodes of atherosclerotic WD-fed Apoe–/– or B6 mice. Data are mean ± SEM of 2 independent experiments. (D) Maximum intensity projection (top view) through image stacks (760 × 760 × 225 μm [x, y, z]). CD11c-YFP+ cells are stained green, SNARF-labeled Apoe–/– CD4+ T cells are stained red, and CMRA-labeled OTII CD4+ T cells are stained blue. No antigen was added. Interacting cells (arrows) were located in the adventitia. See Supplemental Video 7. (E) Mean velocities of individual prestimulated (CD3/CD28) OTII and freely migrating or interacting Apoe–/– CD4+ T cells, isolated from Apoe–/– mice fed WD for 20 weeks. Average is indicated by horizontal line. *P < 0.05; **P < 0.01. Scale bars: 100 μm (A); 30 μm (A, inset); 70 μm (D).