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 allograft-infiltrating 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<sup>+</sup> T cell hyporesponsiveness. While terminally differentiated effector memory cells comprised the majority of peripheral donor-specific CD8<sup>+</sup> T cells in CMV primary infection patients, they were rarely present in liver allografts. Retrospective analysis showed that R<sup>-</sup>D<sup>+</sup> serostatus was an independent protective factor for late acute rejection by multivariate Cox regression analysis (hazard ratio [HR]=0.18, 95% CI=0.04-0.86, p=0.015). Additionally, CMV primary infection patients showed the highest Vδ1/Vδ2 γδ 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. By analyzing the phenotype and alloreactivity of peripheral T cells in humans after liver transplantation, the authors show that primary cytomegalovirus infection is associated with the development of donor-specific CD8+ hyporesponsiveness, and is accompanied by a diminished incidence of late acute rejection and signs of operational tolerance.

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American Journal of Transplantation
Department of Internal Medicine