Primary Cytomegalovirus Infection After Liver Transplantation Is Associated With Attenuated T Cell Alloreactivity and Lower Incidence of Late Acute Rejections.

Abstract

Cytomegalovirus (CMV) infection can induce long-lasting changes of T cell subsets in peripheral blood and is thought to generate alloreactive T cells. However its association with allograft rejection remains controversial in LTx patients. The aim of this study is to determine the effects of CMV primary infection on circulating T cell subsets and T cell alloreactivity after LTx. We monitored peripheral blood CD4+ and CD8+ naïve(TN), central memory(TCM), effector memory(TEM), and late-differentiated effector memory(TEMRA) T cells in 36 patients before, and at 1 and 6 months after LTx. Frequencies of alloreactive T cells, which were defined as T cells specifically upregulate CD137 upon allogeneic stimulation by donor or 3rd-party splenocytes, were compared between CMV primary infection patients (D+/R- with CMV viremia) and CMV naïve patients (D-/R-). As most CMV infections occur within 3 months after LTx, we further retrospectively analyzed the cumulative incidence of clinically relevant late acute rejections (biopsy proven and treated acute rejections occurring more than 3 months after LTx) in our center by Kaplan-Meier method. Six months after LTx, we found CMV primary infection resulted in an expansion of circulating CD8+ TEMRA (from 15% to 57%; p=0.0002), while no difference was observed in CMV naïve patients. CD8+ T cells from CMV primary infection patients (n=14) developed donor-specific hyporesponsiveness (donor-reactive: 0.38%, 3rd party-reactive: 1.00%, p=0.02), while donor and 3rd party-reactive CD8+ T cell frequencies were similar in CMV naïve patients (n=11). CD4+ TEM from CMV primary infection patients contained lower frequencies of both donor and 3rd party-reactive T cells compared to CMV naïve patients (donor-reactive: 2.9% and 6.3% respectively, p=0.02; 3rd party-reactive: 3.6% and 6.6% respectively, p=0.03). In the retrospective analysis, the cumulative incidence of late acute rejections was significantly lower in D+/R- patients (n=119) compared to D-/R- patients (n=114) (3.4% and 14.0% respectively, p=0.01). In conclusion, we found primary CMV infection after LTx is associated with attenuated T cell alloreactivity and lower incidence of late acute rejections. Primary CMV infection may contribute to the development of tolerance to liver grafts.