Cytomegalovirus (CMV) is a ubiquitous virus that presents a significant risk for reactivation or de novo infection in transplant recipients. Clinical transplant tolerance has recently been achieved. In this context, understanding interactions between CMV infection and transplant tolerance is of urgent importance. Methods: Allogeneic heart or islet transplant was performed in a BALB/c⇒B6 combination. Transplant tolerance was induced by infusions of donor splenocytes (SP) chemically fixed with ethylene carbodiimide (ECDI). CMV infection was given by injection of 108 PFU of δm157 MCMV. Results: Acute δm157 infection impaired tolerance induction by ECDI-SP in both heart and islet transplant models. Recipient CD11b+Gr-1+ myeloid derived suppressor cells (MDSCs) were induced by ECDI-SP and are crucial for the tolerance induced by ECDI-SP. This population was significantly depleted by acute δm157 infection. Recipient CD11c+CD11b+ myeliod dendritic cells (DCs) were induced by donor ECDI-SP to express PD-L1 and PD-L2. However, they exhibited a heighened expression of CD80, CD86, and CD40 in the presence of δm157 infection. Consequently, anergy of donor-specific T cells normally induced by donor ECDI-SP was reverted. During tolerance maintenance, acute δm157 infection precipitated graft rejection in 30% recipients. Surprisingly, recipients latently infected with MCMV were also less susceptible to tolerance induction. To examine the effect of tolerance on MCMV reactivation from latency, BALB/c kidneys latently infected with MCMV were transplanted in B6 recipients. Transplanting in non-tolerant recipients led to IE-3 gene expression from the latently infected kidneys, whereas transplanting in tolerant recipients suppressed this expression. Tolerance, however, did not interfere with generation of viral-specific T cells by acute MCMV infection. Conclusions: CMV infection significantly impairs tolerance efficacy, likely via its effects on myeloid cell populations critical for tolerance by ECDI-SP, and donor-specific tolerance effectively suppresses IE gene expression and CMV reactivation. The interaction between CMV infection and tolerance thus warrants future studies to gain critical insight for adequately approaching CMV infection in clinical tolerance.

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