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Fasenmyer Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2013LFA-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\u2212 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.<\/jats:p>","DOI":"10.4049\/jimmunol.2300267","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T15:37:01Z","timestamp":1701704221000},"page":"245-257","source":"Crossref","is-referenced-by-count":10,"title":["Cytomegalovirus Infection Facilitates the Costimulation of CD57+CD28\u2212 CD8 T Cells in HIV Infection and Atherosclerosis via the CD2\u2013LFA-3 Axis"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5400-5320","authenticated-orcid":false,"given":"Nicole E","family":"Winchester","sequence":"first","affiliation":[{"name":"Cleveland Clinic Lerner College of Medicine at Case Western Reserve University , Cleveland, 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MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3232-8329","authenticated-orcid":false,"given":"Stephen R","family":"Morris","sequence":"additional","affiliation":[{"name":"Louis Stokes Cleveland Veterans Affairs Medical Center , Cleveland, OH"},{"name":"Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine , Miami, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M","family":"Clagett","sequence":"additional","affiliation":[{"name":"Rustbelt Center for AIDS Research, Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University\/University Hospitals Cleveland Medical Center , Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4648-6942","authenticated-orcid":false,"given":"Steven M","family":"Juchnowski","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Case Western Reserve University\/University Hospitals Cleveland Medical Center , Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghavendra","family":"Yadavalli","sequence":"additional","affiliation":[{"name":"Rustbelt Center for AIDS Research, Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University\/University Hospitals Cleveland Medical Center , Cleveland, OH"},{"name":"Department of Immunoassay, ICON plc , Whitesboro, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Villinger","sequence":"additional","affiliation":[{"name":"New Iberia Research Center, University of Louisiana at Lafayette , New Iberia, LA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Paiardini","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University , Atlanta, GA"},{"name":"Department of Pathology and Laboratory Medicine, Emory University School of Medicine , Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karem","family":"Harth","sequence":"additional","affiliation":[{"name":"Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center\/Case Western Reserve University , Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1780-979X","authenticated-orcid":false,"given":"Vikram S","family":"Kashyap","sequence":"additional","affiliation":[{"name":"Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center\/Case Western Reserve University , Cleveland, OH"},{"name":"Meijer Heart and Vascular Institute, Corewell Health , Grand Rapids, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard H","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Department of Rheumatic and Immunologic Diseases, Cleveland Clinic , Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonid","family":"Margolis","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1769-8682","authenticated-orcid":false,"given":"Scott F","family":"Sieg","sequence":"additional","affiliation":[{"name":"Rustbelt Center for AIDS Research, Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University\/University Hospitals Cleveland Medical Center , Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6908-1246","authenticated-orcid":false,"given":"Carey 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