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

Abstract

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 cells in vitro.

CD8+ T Cells in Atherosclerosis

“…CD8 + T cells are recruited to the inflamed vessel wall in atherosclerosis [ 8 ]. Little is still known about how CD8 + T cells migrate to lesion sites, but CX3CR1 was recently uncovered to direct CD8 + T cells into lesions in humans [ 47 ].…”

“…However, less is known about how CD8 + T cells migrate to the lesion sites. A CD8 + T cell population expressing the endothelium homing receptor CX3CR1 was recently described in humans [ 46 , 47 ] that may be directed by CX3CL1-expressing endothelial cells to the inflamed vessel wall [ 47 ].…”

Inflammatory Markers Related to Innate and Adaptive Immunity in Atherosclerosis: Implications for Disease Prediction and Prospective Therapeutics

“… 81 Several chemokines released in the atherosclerotic lesion milieu are involved in the recruitment of the CD8 + T cells, which may then stimulate apoptosis in other immune cells and VSMCs, resulting in the development of lesions and related adverse complications. 82 , 83 One of the functions of the natural killer (NK) T (NKT) cells is to recognize lipid antigens presented by CD1 molecules on several cells. The activated NKT cells generate diverse inflammatory mediators that augment the development of atherosclerosis.…”

Inflammatory Chemokines in Atherosclerosis

“…Furthermore, a recent study has highlighted a novel model of CD8 T cell involvement in atherosclerosis. Whereby CX3CL1 and IL-15 synergistically activate the vascular endothelium to promote infiltration of CX3CR1 + memory CD8 T cells which further promote endothelial inflammation [ 140 ]. This interaction may be prevalent in aging and in HIV populations where circulating activated CX3CR1 + CD8 T cell numbers are often higher.…”