CX3CL1 and IL-15 Promote CD8 T cell chemoattraction in HIV and in atherosclerosis

Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cellsin vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent within vivoIL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded. Author summary People living with HIV infection and elderly HIV-uninfected persons have increased risk of developing atherosclerotic cardiovascular disease, and have increased numbers and/or proportions of CD8 T cells that express the vascular endothelium-homing receptor CX3CR1. Atherosclerotic plaques contain many activated CD8 T cells, which have been implicated in disease pathogenesis, yet the mechanisms driving T cell recruitment to and activation within plaques are not clear. Here we propose a model in which CX3CR1+ CD8 T cells promote endothelial dysfunction by the combined effects of CX3CL1, IL-15, and TNF. Persistent inflammation triggers endothelial cell activation and dysfunction in people living with HIV infection. Endothelial cell-derived CX3CL1 then directs the migration of CX3CR1+ T cells to the activated endothelium where IL-15 activates T cells to express TNF. TNF drives endothelial expression of CX3CL1 and IL-15, providing a feed-forward loop of activation. We provide evidence that these pathways are active in human atherosclerotic plaques and in the aortic endothelium of SIV/SHIV-infected rhesus macaques. We propose these mechanisms of T cell-induced endothelial damage are operative in traditional risk factor-associated atherosclerosis in the general population and are accelerated in people with HIV infection who live in a state of sustained chronic inflammation.