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

Soumya Panigrahi, Bonnie Chen, Mike Fang, Daria Potashnikova, Alexey A. Komissarov, Anna Lebedeva, Gillian M. Michaelson, Jonathan M. Wyrick, Stephen R. Morris, Scott F. Sieg, Mirko Paiardini, Francois J. Villinger, Karem Harth, Vikram S. Kashyap, Mark J. Cameron, Cheryl M. Cameron, Elena Vasilieva, Leonid Margolis, Souheil Antoine Younes, Nicholas T. FunderburgDavid A. Zidar, Michael M. Lederman, Michael L. Freeman

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-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.

Original languageEnglish (US)
Article number1008885
JournalPLoS pathogens
Volume16
Issue number9
DOIs
StatePublished - Sep 2020

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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