title: Expansion of effector memory TCR Vbeta4+ CD8+ T cells is associated with latent infection-mediated resistance to transplantation tolerance.
abstract: 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 gammaHV68, a murine gamma-herpesvirus closely related to human gamma-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, gammaHV68-infected mice showed increased frequency of CD8+ T cell alloreactivity and, interestingly, expansion of virus-induced, alloreactive, "effector/effector memory" TCR Vbeta4+CD8+ T cells driven by the gammaHV68-M1 gene was associated with resistance to tolerance induction in studies using gammaHV68-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.
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Stapler
authors.forename: Eun D
authors.initials: ED
authors.lastname: Lee
authors.forename: Saranya A
authors.initials: SA
authors.lastname: Selvaraj
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Evans
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Kean
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Speck
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.forename: Shivaprakash
authors.initials: S
authors.lastname: Gangappa
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D019674:Genes, T-Cell Receptor beta; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D006566:Herpesviridae Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D007113:Immunity, Innate / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera / Q000276:immunology; D018144:Rhadinovirus / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*; D017735:Virus Latency / Q000235:genetics / Q000276:immunology*