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.

Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs

“…For example, is DC-mediated T cell activation occurring in draining lymph nodes, followed by T cell homing to lesions, or might there also be DC/T cell activation occurring in the lesions themselves? A recent study demonstrated productive interaction of CD4 + T cells with CD11c hi cells in the vascular wall of atherosclerotic lesions ex vivo, suggesting that lesional CD11c hi DCs could activate T cells in the atherosclerotic lesions in vivo (19). In this context, we observed decreased Treg numbers not only in aorta-draining iliac and mediastinal lymph nodes of Cre + mice, but also in the nondraining inguinal lymph nodes (Supplemental Figure 11).…”

“…One hypothesis for the presence of activated T cells in atherosclerotic lesions is DC-mediated presentation of antigens to T cells in peripheral lymph nodes and perhaps the lesions themselves (5,19). As shown in Figure 2A, analysis of aorta-draining iliac lymph nodes demonstrated that the naive/effector T cell ratio was significantly higher in the Cre + mice and the percentage of Tregs was lower, while the total T cell numbers were unaffected (data not shown).…”

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

“…Although proatherogenic T cell responses could plausibly occur in any secondary lymphoid tissue, effector T cells must migrate into the arterial wall and be locally activated by APCs to influence lesion development. Both DCs and lesional macrophages, including cholesterol-loaded foam cells (130,131), likely participate in the local activation of effector CD4 + and CD8 + T cells. In addition, stimulation of plasmacytoid DCs also plays an atherogenic role (132).…”

Flow-dependent expression of ectonucleotide tri(di)phosphohydrolase-1 and suppression of atherosclerosis

“…Development of atherosclerotic plaque is driven by dynamic interactions among the lipid milieu, fluid shear forces, cells of the vascular wall, and cells recruited from the circulation. Endothelial cells, monocytes, T cells, and platelets have all been implicated in atherogenesis (2)(3)(4). Recent studies have described the role of platelet activation in the early stages of atherogenesis via transient endothelial and mononuclear interactions and in situ release of mitogens and chemoattractants (5,6).…”