The role of CD8+ T cells in medullar monocyte generation and atherosclerosis

点击翻译按钮获取中文摘要

Atherosclerosis, the main cause of ischemic diseases such as myocardial infarction and stroke, is now widely recognized as a chronic inflammatory disease of the vascular wall in which immune cells both locally and systemically control lesion progression. A previously unrecognized pro-atherogenic role of CD8+ T cells is emerging, which appears to depend on the CD8+ T cell-mediated promotion of macrophage accumulation within plaques. A recent study by our group demonstrated that during early atherogenesis, this process mostly relied on CD8+ T cell-induced activation of monocyte production in the bone marrow. Besides hosting the hematopoietic stem cell niche, it is now increasingly recognized that bone marrow plays an active role as an immune regulatory organ. We here hypothesize that CD8+ T cells are locally activated in BM to upregulate cytokine expression under conditions of hypercholesterolemia, and that activated bone marrow CD8+ T cells induce local bone marrow inflammation, thereby promoting monopoiesis and atherosclerosis. To experimentally address this, we will perform a comprehensive investigation of the changes in bone marrow during Wester type diet feeding in atherosclerosis-prone mice, which induces hypercholesterolemia and atherosclerotic lesion formation. We will investigate whether bone marrow CD8+ T cells are activated locally and antigen-specifically under conditions of hypercholesterolemia and whether this is mediated by antigen-presenting cells in the bone marrow. Adoptive transfer experiments into atherosclerosis-prone mice deficient in CD8+ T cells and fed a Western Diet will furthermore be performed using different donor CD8+ T cell subsets from bone marrow and other compartments to further unravel whether such activated CD8+ T cell subsets trigger local inflammation in the bone marrow to promote monopoiesis and atherosclerosis, and to address, whether this is IFNgamma-dependent. Altogether, this project will deepen our understanding of the complex role of the bone marrow niche in atherosclerosis and provide us with novel insights into the emerging role of CD8+ T cells in atherogenesis.