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, however the mechanisms remain poorly understood. PAR1 connects the coagulation cascade, endothelial cells and CD8 T cells at the site of endothelial inflammation and we hypothesized that HIV driven CD8 T cell immune activation alters endothelial repair mechanisms. Endothelial repair is partially mediated by angiogenic T (T ) cells that facilitate proliferation of endothelial cells, and differentiation of endothelial progenitor cells at site of vascular injury. During LCMV infection, we identified a subset of CD31 CD8 T cells that exhibited a long-lived memory precursor phenotype (CD127 KLRG1 ) and secreted the proangiogenic cytokine vascular endothelial growth factor (VEGF) after viral control. Furthermore, in PWH, the frequencies of CD8 T cells were reduced and showed an activated phenotype and expression of granzymes. GZMA GZMB CD8 T cells correlated with atherosclerotic cardiovascular disease (ASCVD) risk. , granzyme dependent PAR1 activation led to calcium mobilization and secretion of proinflammatory cytokines IL-6, IL-8 and angiopoietin-2 by primary human endothelial cells. Altogether, these findings suggest that CD8 T cells are involved in immunity against viruses and endothelial homeostasis and HIV driven immune activation alters these functions.