Mechanisms of CD8+ mediated cell non-autonomous arterial aging

PROJECT SUMMARY: Aging is the most predictive risk factor for cardiovascular disease. Aged arteries exhibit increased large artery stiffness and blunted endothelium dependent dilation; both of these changes occur prior to the onset of overt cardiovascular disease, such as atherosclerosis or stroke. Several lines of evidence have supported the

emerging concept of cell non-autonomous aging, where signals arising from one cell type can drive the degenerative process of aging in other types of cells. Consistent with this concept, we have recently shown that T cells play a critical role in the development of age-related arterial stiffening and impairments in arteriolar

endothelium dependent dilation. Despite this observation the T cell subtype(s), the mechanisms that result in T cell accumulation around the arteries and how T cells influence the cells of the artery remain unclear. We have found substantial age-related accumulation of memory CD8+ T cells making proinflammatory cytokines in the

aorta and in the mesenteric vasculature. Eomesodermin (Eomes) is a transcription factor that drives many features consistent with CD8+ T cell aging. We have observed increased Eomes protein in both splenic CD8+ T cells as well as those that accumulate in the arteries with age. In addition to alterations in CD8+ phenotype,

CD8+ trafficking also appears to be altered with age. CCL5 is a chemokine that is a potent T cell recruiter. Interestingly, our preliminary data indicates that CD8+ cells themselves generate CCL5, potentially initiating a feed forward cascade where CD8+ derived CCL5 recruit more T cells to the arteries driving arterial

inflammation and cell non-autonomous arterial aging. In preliminary observations, we have also observed increased CD8+ proinflammatory cytokine production and increased proportions of Eomes expressing cells in CD8+ cells from older human donors, supporting translational potential. These observations lead to the

hypothesis that both the memory/proinflammatory phenotype of CD8+ and altered CD8+ T cell trafficking drive cell non-autonomous arterial aging. To test this hypothesis, we will assess the phenotype of immune cells accumulating in the arteries, the phenotype of the artery, large artery stiffness and endothelium dependent

dilation in arteries from a range of mouse models including: pharmacological and genetic deletion of T cell subtypes and adoptive transfer of young and old T cells to T cell deficient mice, as well as, pharmacological and genetic inhibition of CCL5 signaling and adoptive transfer of CCL5 deficient T cells. We will also determine

whether Eomes and CCL5 signaling is associated with impaired endothelium dependent dilation and arterial stiffness in older adults. Lastly, we will employ cell culture models to determine whether CD8+ T cells from older adults can directly induce cellular changes consistent with fibrosis and endothelial dysfunction. The results of

these studies will provide translational and mechanistic insight into the role of aged CD8+ T cell in cell non- autonomous arterial aging and identify targets for intervention to preserve health with age.