Bootcongres

Alloreactive T cells mediate allograft rejection after liver transplantation (LTx). Cytomegalovirus (CMV) infection can induce long-lasting changes of T cell subsets in peripheral blood and is thought to generate alloreactive T cells. However the association between CMV infection and T cell alloreactivity is still 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 the percentages of peripheral blood CD4⁺ and CD8⁺ T_N (naïve),T_CM (central memory), T_EM (effector memory), and T_EMRA (late-differentiated effector memory) in 36 patients before, and at 1 and 6 months after LTx. Frequencies of alloreactive T cells, which were defined as T cells that specifically upregulate CD137 upon allogeneic stimulation by donor or 3^rd-party splenocytes, were compared between CMV primary infection patients (D⁺/R^- with CMV viremia) and CMV naïve patients (D^-/R^-). As most CMV infection occurs within 3 months after LTx, we further retrospectively analyzed the cumulative incidence of clinically relevant late acute rejection (LAR, 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 CD8⁺ T_EMRA (from 15% to 57%; p=0.0002) at the cost of decreased percentage of CD8⁺ T_N (from 66% to 17%; p< 0.0001), while no difference was observed in CMV naïve patients. CD4⁺ T_EM from CMV primary infection patients (n=14) contained lower frequencies of both donor and 3^rd party-reactive T cells compared to CMV naïve patients (n=11) (donor-reactive: 2.9% and 6.3% respectively, p=0.02; 3^rd party-reactive: 3.6% and 6.6% respectively, p=0.03). CD8⁺ T cells from CMV primary infection patients developed donor-specific hypo-responsiveness (donor-reactive: 0.38%, 3^rd party-reactive: 1.00%, p=0.02), while donor and 3^rd party-reactive CD8⁺ T cell frequencies were similar in CMV naïve patients. In the retrospective analysis, cumulative incidence of late acute rejection 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 clinically relevant late acute rejections.