Cytomegalovirus Infection Facilitates the Costimulation of CD57+CD28− CD8 T Cells in HIV Infection and Atherosclerosis via the CD2–LFA-3 Axis
Year: 2023
Type: article
Abstract: CD8 T cells are emerging as important mediators in atherosclerosis and cardiovascular disease (CVD). Immune activation may play a particular role in people with HIV (PWH) who are at an increased risk of CVD, even after controlling for known CVD risk factors. Latent CMV infection is associated with increased CVD risk for both PWH and people without HIV, and human CMV-specific CD4 and CD8 T cells are enriched for an immunosenescent phenotype. We previously showed that CMV coinfection in PWH promotes vascular homing and activation of inflammatory CD4 T cells through the CD2-LFA-3 axis. However, the role of CD2/LFA3 costimulation of CD8 T cells in PWH with CMV has yet to be described. In the present study, we demonstrate that CD2 expression on CX3CR1+CD57+CD28- inflammescent CD8 T cells is increased on cells from CMV-seropositive PWH. In vitro CD2/LFA-3 costimulation enhances TCR-mediated activation of these inflammatory CD8 memory T cells. Finally, we show that LFA-3 is highly expressed in aortas of SIV-infected rhesus macaques and in atherosclerotic plaques of people without HIV. Our findings are consistent with a model in which CMV infection enhances CD2 expression on highly proinflammatory CD8 T cells that can then be stimulated by LFA-3 expressed in the vasculature, even in the absence of CD28 costimulation. This model, in which CMV infection exacerbates toxic cytokine and granzyme production by CD8 T cells within the vasculature, highlights a potential therapeutic target in atherosclerosis development and progression, especially for PWH.
Source: The Journal of Immunology
Authors: Nicole E Winchester, Soumya Panigrahi, Anokhi Haria, Archeesha Chakraborty, Xi Su, Bonnie Chen, Stephen R Morris, Brian M Clagett, Steven M Juchnowski, Raghavendra Yadavalli, Francois Villinger, Mirko Paiardini, Karem Harth, Vikram S Kashyap, Leonard H Calabrese, Leonid Margolis, Scott F Sieg, Carey L Shive, Sara Gianella, Nicholas T Funderburg, David A Zidar, Michael M Lederman, Michael L Freeman
Institutions: Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, University Hospitals of Cleveland, University Hospitals Cleveland Medical Center, Carnegie Mellon University, University of Missouri, University of Miami, Louis Stokes Cleveland VA Medical Center, University of Louisiana at Lafayette, Emory University, Emory National Primate Research Center, Corewell Health, Cleveland Clinic, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, University of California San Diego, The Ohio State University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Impact of Reproductive Aging On HIV Persistence and Inflammation, SPF Breeding Colonies at the Yerkes NPRC, G2898952431, G376641150, Mechanisms of CMV Replication on HIV Persistence, Determining the mechanisms of vascular CD8 T cell activation in CMV and HIV infections, Targeting Cytolytic Cells to Lymphoid Sites of HIV Persistence., G4559000102, Targeting Cytolytic Cells to Lymphoid Sites of HIV Persistence., G5028759665, G6314521394, G6428942787, Overcoming restrained lung trafficking by memory CD4+ T cells to prevent active tuberculosis in people living with HIV, G858481422, G8669742766, Rustbelt Center for AIDS Research (Case/UHC-Pitt CFAR), Maintenance of the SPF Breeding Colonies at Yerkes National Primate Research Center, HOPE - HIV Obstruction by Programmed Epigenetics, Emory National Primate Research Center
OpenAlex ID: W4389305509