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

• Type of Material: Article
• Authors: Soumya Panigrahi, Case Western Reserve University; Bonnie Chen, Case Western Reserve University; Mike Fang, Case Western Reserve University; Daria Potashnikova, Moscow State University of Medicine & Dentistry; Alexey A. Komissarov, Moscow State University of Medicine & Dentistry; Anna Lebedeva, Moscow State University of Medicine & Dentistry; Gillian M. Michaelson, Case Western Reserve University; Jonathan M. Wyrick, Case Western Reserve University; Stephen R. Morris, Cleveland Louis Stokes Veteran Affairs Medical Center; Scott F. Sieg, Case Western Reserve University; Mirko Paiardini, Emory University; Francois Villinger, Emory University; Karem Harth, Case Western Reserve University; Vikram S. Kashyap, Case Western Reserve University; Mark J. Cameron, Case Western Reserve University; Cheryl M. Cameron, Case Western Reserve University; Elena Vasilieva, Moscow State University of Medicine & Dentistry; Leonid Margolis, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Souheil Younes, Emory University; Nicholas T. Funderburg, Ohio State University; David A. Zidar, Cleveland Louis Stokes Veteran Affairs Medical Center; Michael M. Lederman, Case Western Reserve University; Michael L. Freeman, Case Western Reserve University
• Language: English
• Date: 2020-09-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1008885
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 16
• Issue: 9
• Start Page: e1008885
• End Page: e1008885
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH) (www.nih.gov) grant OD11132 in support of the Yerkes National Primate Research Center to M.P.; NIH grant HL134544 to N.T.F.; the Clinical and Translational Science Collaborative of Cleveland (KL2TR000440) to D.A.Z; NIH grants (AI076174, AI069501) and the Richard J. Fasenmyer Foundation awarded to M.M.L.; and the CWRU Center for AIDS Research Catalytic Awards (AI036219) to D.A.Z. and M.L.F. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: CHEMOKINE RECEPTOR CX3CR1; Life Sciences & Biomedicine; ENDOTHELIAL-CELLS; MIGRATION; DISEASE; CARDIOVASCULAR RISK; Science & Technology; RHEUMATOID-ARTHRITIS; Parasitology; EXPRESSION; Microbiology; Virology; INTERLEUKIN-15; FRACTALKINE; ACTIVATION
• Research Categories: Biology, Parasitology; Biology, Microbiology; Biology, Virology

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.