Angiogenic CD8 T cells from PWH induce Granzymes-dependent PAR1 activation promoting endothelial inflammation

In people with HIV (PWH), T cell immune activation and endothelial inflammation are contributors of the increased cardiovascular risk but the mechanisms remain poorly understood. In this study, we hypothesized that immune activation alters angiogenetic CD8 T cell (T ang ) function driving endothelial chronic inflammation. Endothelial cell repair is partially mediated by angiogenic T (T ang ) cells which facilitate proliferation and differentiation of bone marrow derived and resident endothelial progenitor cells at site of vascular injury. The role of CD8 T ang cells in the setting of viral infection, including chronic HIV infection is largely unknown. In this study, we identified a subset of CD8 T cells expressing CD31 high that exhibited a long-lived memory precursor phenotype (CD127 + KLRG1 - ) and secreted the pro-angiogenic cytokine vascular endothelial growth factor (VEGF) in mice infected with acute LCMV. Furthermore, in PWH, the frequencies of circulating CD8 T ang cells were reduced and showed an activated phenotype and expression of granzymes. GZMA + GZMB + CD8 T ang cells correlated with atherosclerotic cardiovascular disease (ASCVD) risk. In vitro , granzyme dependent PAR1 activation led to calcium mobilization and secretion of pro-inflammatory cytokines IL-6, IL-8 and Angiopoietin-2 by primary human endothelial cells. Altogether, these findings suggest that HIV driven activation of CD8 T ang cells promotes endothelial inflammation and chronic stimulation of this pathway may contribute to the increased risk of cardiovascular disease in PWH.