A tissue-specific phenotype for CD8+T cells in atherosclerotic lesions: role of the arterial microenvironment

Abstract

Atherosclerosis is a chronic, inflammatory disorder of the arterial wall that causes millions of deaths worldwide each year. CD8+ T lymphocytes may play an important role in atherogenesis, as they represent 29% of all lymphocytes in early human lesions, increasing up to 50% in advanced plaques, however their contribution to plaque initiation and progression remains unclear. Here we show that CD8+ T cells derived from enzymatically digested atherosclerotic lesions of ApoE−/− mice display a unique phenotype. Most notably, lesion derived CD8+ T cells produce less IFN-γ and TNF-α after PMA/Ionomycin stimulation compared to their counterparts in the spleen, circulation or other non-lymphoid organs. Importantly, cytokine production decreases as the lesion progresses to more advanced stages. This effect is not due to classical exhaustion of the T cells, as we found no difference in the expression of exhaustion markers such as PD-1. Nor is this effect due to an increase in regulatory FoxP3+CD8+ T cells. Together, our results suggest that the specific atherosclerotic environment in the vessel wall decreases CD8+ T cell functionality, which provides a new understanding of CD8+ T cells and their role in the pathogenesis of atherosclerosis.