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Cytomegalovirus-Infected Human Endothelial Cells Can Stimulate Allogeneic CD4⁺ Memory T Cells by Releasing Antigenic Exosomes¹

Jason D. Walker^*, Cheryl L. Maier and Jordan S. Pober^2,

^* Department of Genetics and Department of Immunobiology, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT 06520

Human CMV infection is controlled by T cell-mediated immunity and in immunosuppressed transplant patients it is associated with acute allograft rejection as well as chronic allograft vasculopathy. CMV infects endothelial cells (EC) and it is thought that CMV-specific host immune responses to infected allograft EC contribute to rejection. In vitro, CD4⁺ T cells from CMV-positive donors (but not CMV-negative donors) are readily activated by CMV-infected allogeneic EC, although it is unclear how allogeneic CMV-infected EC activate self-class II MHC-restricted memory CD4⁺ T cells. In this study, we confirm that purified CD4⁺ T cells from CMV⁺ donors are activated by allogeneic CMV-infected EC, but find that the response is dependent upon copurified APC expressing class II MHC that are autologous to the T cells. The transfer of CMV Ags from infected EC to APC can be mediated by EC-derived exosome-like particles. These results provide a mechanism by which CMV can exacerbate allograft rejection and suggest a novel function of EC-derived exosomes that could contribute in a more general manner to immune surveillance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grant HL-051014 (to J.S.P.). Additional support for J.D.W. was provided by: the National Science Foundation Graduate Research Fellowship Program; the John F. Enders Professorship endowment to Dr. George Miller, Department of Pediatrics, Yale University School of Medicine; and the Waldemar Von Zedtwitz Professorship endowment to Dr. Daniel DiMaio, Department of Genetics, Yale University School of Medicine.

² Address correspondence and reprint requests to Dr. Jordan S. Pober, Yale University, School of Medicine, 10 Amistad Street, Room 401D, New Haven, CT 60520-8089. E-mail address: jordan.pober{at}yale.edu

³ Abbreviations used in this paper: EC, endothelial cell; CPE, cytopathic effect; gB, glycoprotein B; UV-CMV, UV-inactivated CMV; DC, dendritic cell.