CMV Primary Infection Is Associated With Donor-Specific T Cell Hyporesponsiveness and Fewer Late Acute Rejections After Liver Transplantation

Abstract

Viral infections, including cytomegalovirus (CMV), abrogate transplantation tolerance in animal models. Whether this also occurs in humans remains elusive. We investigated how CMV affects T cells and rejection episodes after liver transplantation (LT). Phenotype and alloreactivity of peripheral and allograftinfiltrating T cells from LT patients with different CMV status were analyzed by flow cytometry. The association of CMV status with early and late acute rejection was retrospectively analyzed in a cohort of 639 LT patients. CMV-positivity was associated with expansion of peripheral effector memory T cell subsets after LT. Patients with CMV primary infection showed donor-specific CD8 þ T cell hyporesponsiveness. While terminally differentiated effector memory cells comprised the majority of peripheral donor-specific CD8 þ T cells in CMV primary infection patients, they were rarely present in liver allografts. Retrospective analysis showed that R À D þ serostatus was an independent protective factor for late acute rejection by multivariate Cox regression analysis (hazard ratio [HR] ¼ 0.18, 95% CI ¼ 0.04-0.86, p ¼ 0.015). Additionally, CMV primary infection patients showed the highest Vd1/Vd2 gd T cell ratio, which has been shown to be associated with operational tolerance after LT. In conclusion, our data suggest that CMV primary infection may promote tolerance to liver allografts, and CMV status should be considered when tapering or withdrawing immunosuppression.

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…Similar observations have been made in healthy CMV-seropositive patients and bone marrow recipients (193). Some observations favor a role for cd T cells in tolerance (194). In liver transplantation, cd T cell genes were included in the gene expression signature of tolerant recipients (195), and intragraft cd T cell infiltration was associated with pediatric liver transplant tolerance (196).…”

“…In this series, reduced alloreactivity and improved graft function were found in patients with strong CMV IE1-specific T cell responses up to 6 mo after transplantation (159). In liver transplant recipients, CMV seropositivity was associated with expansion of peripheral effector memory T cell subsets (160). Patients with primary CMV infections demonstrated donor-specific CD8+ T cell hyporesponsiveness.…”

“…In primary CMV infections, terminally differentiated effector-memory cells composed the majority of peripheral donor-specific CD8+ T cells but were rarely present in liver allografts; however, in retrospective analysis, donorseropositive and recipient-seronegative serostatus mismatch remains as an independent protective factor for late acute rejection (160).…”

Cytomegalovirus-Induced γδ T Cells During Rejection: An Ambivalent T Cell

“…From a large cohort, Shi et al recently observed that cytomegalovirus (CMV) DþR-serostatus was associated with protection against late acute rejection of liver allografts (1). Although this finding appears very interesting, some immunological hypotheses proposed in this article deserve several comments.…”

Reply to “Cytomegalovirus-Induced γδ T Cells During Rejection: An Ambivalent T Cell”

“…We would like to thank Bachelet et al (1) for their comments on our recent paper (2), in which we reported that primary cytomegalovirus (CMV) infection after liver transplantation (LT) is associated with donor-specific CD8 þ T-cell hyporesponsiveness, and with a reduced acute rejection incidence late after transplantation. These observations surprised us, because they suggest that primary CMV infection may be associated with development of immunological tolerance to liver allografts, contrasting to findings from previous animal studies.…”