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Expansion of Effector Memory TCR Vβ4⁺CD8⁺ T Cells Is Associated with Latent Infection-Mediated Resistance to Transplantation Tolerance¹

Dale Stapler^*, Eun D. Lee^*, Saranya A. Selvaraj^*, Andrew G. Evans, Leslie S. Kean^*, Samuel H. Speck, Christian P. Larsen^* and Shivaprakash Gangappa^2,*

^* Emory Transplant Center, Department of Surgery and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322

Therapies that control largely T cell-dependent allograft rejection in humans also possess the undesirable effect of impairing T cell function, leaving transplant recipients susceptible to opportunistic viruses. Prime among these opportunists are the ubiquitous herpesviruses. To date, studies are lacking that address the effect of viruses that establish a true latent state on allograft tolerance or the effect of tolerance protocols on the immune control of latent viruses. By using a mixed chimerism-based tolerance-induction protocol, we found that mice undergoing latent infection with HV68, a murine -herpesvirus closely related to human -herpesviruses such as EBV and Kaposi’s sarcoma-associated herpesvirus, significantly resist tolerance to allografts. Limiting the degree of virus reactivation or innate immune response did not reconstitute chimerism in latently infected mice. However, HV68-infected mice showed increased frequency of CD8⁺ T cell alloreactivity and, interestingly, expansion of virus-induced, alloreactive, "effector/effector memory" TCR Vβ4⁺CD8⁺ T cells driven by the HV68-M1 gene was associated with resistance to tolerance induction in studies using HV68-M1 mutant virus. These results define the viral gene and immune cell types involved in latent infection-mediated resistance to allograft tolerance and underscore the influence of latent herpesviruses on allograft survival.

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 by National Institutes of Health Grant P01 AI04464409 (to C.P.L.) and the American Society of Transplantation/Astellas Basic Science Faculty Development grant (to S.G.).

² Address correspondence and reprint requests to Dr. Shivaprakash Gangappa, Department of Surgery, 101 Woodruff Circle, WMB, Suite 5203, Emory University School of Medicine, Atlanta, GA 30322. E-mail address: sgangap{at}emory.edu

³ Abbreviations used in this paper: BM, bone marrow; HV68, -herpesvirus 68; KSHV, Kaposi’s sarcoma-associated herpesvirus; ORF, open reading frame; p.i., postinoculation; T_E, effector CD8⁺ T cell subset; T_EM, effector memory subset of memory CD8⁺ T cell populations; T_CM, central memory subset of CD8⁺ T cell populations; T_N, naive CD8⁺ T cell subset.