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

• 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
• Journal Title: PLOS PATHOGENS
• Volume: Volume 16, Number 9
• Publisher: PUBLIC LIBRARY SCIENCE | 2020-09-01, Pages e1008885-e1008885
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.ppat.1008885
• Subjects: Biology, Microbiology; Biology, Virology; Biology, Parasitology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Microbiology; Parasitology; Virology; CHEMOKINE RECEPTOR CX3CR1; RHEUMATOID-ARTHRITIS; CARDIOVASCULAR RISK; ENDOTHELIAL-CELLS; EXPRESSION; FRACTALKINE; ACTIVATION; MIGRATION; DISEASE; INTERLEUKIN-15

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.