mTOR inhibitors prevent CMV infection through the restoration of functional αβ and γδ T cells in kidney transplantation
Association of mTOR-inhibitors (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in CMV-seropositive (R+) kidney transplant recipients (KTR) remains unexplained. We hypothesized that CMV infection in R+ patients could be due to dysfunctional T cells that might be improved by mTORi. First, in R+ KTR receiving mycophenolic acid (MPA), we showed that both alpha-beta and gamma-delta T-cells displayed a more dysfunctional phenotype (LAG3+, TIM3+, PD-1+, CD85j+) at day 0 of transplantation in the 16 KTR with severe CMV infection when compared to the 17 KTR without or with spontaneously resolving CMV infection. Second, in patients treated with mTORi (n= 27), the proportion of PD-1+ and CD85j+ gamma-delta and alpha-beta T-cells decreased when compared to MPA-treated patients (n=44), as the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of late-differentiated and cytotoxic alpha-beta T-cells, IFNgamma producing and cytotoxic alpha-beta T-cells. In vitro, mTORi (i) increased proliferation, viability and CMV-induced IFNgamma production of alpha-beta and gamma-delta T-cells, (ii) decreased PD-1 and CD85j expression in both subsets that shifted to a more efficient EOMES low Hobit high profile. In gamma-delta T-cells mTORi effect was related to increased TCR signaling. Our results reveal (i) that severe CMV replication is associated with a dysfunctional T cell profile and (ii) that mTORi improve their fitness in association with a better control of CMV. Dysfunctional T cell phenotype could represent a new biomarker to predict post-transplantation infection if KTR received MPA and to stratify patients who should benefit from mTORi treatment.