Expansion of effector memory TCR Vβ4+ CD8+ T cells is associated with latent infection-mediated resistance to transplantation tolerance

D Stapler, ED Lee, SA Selvaraj, AG Evans… - The Journal of …, 2008 - journals.aai.org
D Stapler, ED Lee, SA Selvaraj, AG Evans, LS Kean, SH Speck, CP Larsen, S Gangappa
The Journal of Immunology, 2008journals.aai.org
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 …
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 γHV68, a murine γ-herpesvirus closely related to human γ-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, γHV68-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 γHV68-M1 gene was associated with resistance to tolerance induction in studies using γHV68-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.
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