Background: Transplantation tolerance in human recipients has been achieved in recent trials. Nevertheless, the impact of highly prevalent and clinically relevant cytomegalovirus (CMV) infection on the stability of transplantation tolerance is yet to be determined. We thus investigated the impact of CMV infection on established transplantation tolerance in the recipients with stable graft function.

Methods: A fully allogeneic islet transplantation model was used (Balb/c to C57BL/6J). Transplantation tolerance was induced by infusing donors apoptotic splenocytes pre-treated with chemical cross-linker ethylcarbodiimide (ECDI-SP) on day -7 and +1, with day 0 being the day of transplantation. Tolerized recipients with functional islets (normoglycemic) for >90 days were infected with murine CMV strain [Delta]m157 on day 95 post-transplantation. Blood glucose levels were used as a readout of graft-function.

Results: Infusion of ECDI-SP induced the transplantation tolerance and these recipients carried functional islet-cell grafts indefinitely. Following MCMV infection on day 95 post transplantation, a significant number of the previously tolerized recipients lost graft-function within 2-4 weeks of the infection. The uninfected tolerant recipients contained intragraft CD44⁺ CD4 T cells expressing high levels of CD73, folate receptor (FR)-4, and PD1 (anergic phenotype). These anergic T cells comprised of both Foxp3 (+) and (-) populations. Interestingly, post MCMV infection, the anergic phenotype of intragraft CD4 T cells was lost with the number of CD73^HIFR4^HIPD1⁺ CD4 T cells drastically reduced. Ensuing the loss of anergic phenotype of CD4 T cells, graft destruction and recurrent hyperglycemia followed.

Conclusion: It has previously been shown that multiple pathways including clonal deletion, anergy, Foxp3⁺ regulatory T cells, and PD1/PDL1 signaling may in combination contribute to the maintenance of transplantation tolerance. Our data indicate that interference with the intragraft CD73^HIFR4^HIPD1⁺ anergic CD4 T cells by acute MCMV infection may contribute to the disruption of established transplantation tolerance. Mechanism/s of MCMV infection leading to the loss of anergic CD4 T cell phenotype and the direct causality of this loss to the ensuing graft destruction are currently under investigation.

CITATION INFORMATION: Dangi A., Zhang L., Zhang X., Luo X. Acute Murine CMV Infection Results in Loss of Intragraft CD73^HIFR4^HIPD1⁺ CD4 T Cells and Graft Rejection in Previously Tolerant Recipients Am J Transplant. 2017;17 (suppl 3).

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