mTOR Inhibitors Prevent CMV Infection through the Restoration of Functional αβ and γδ T cells in Kidney Transplantation

Background: The reported association of mTOR-inhibitor (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in CMV-seropositive (R+) kidney transplant recipients (KTR) remains unexplained. Methods: The incidence of CMV infection and T-cell profile was compared between mTORi- treated and mycophenolic acid (MPA)-treated KTR, and mTORi effects in vitro on T-cell phenotype and functions analyzed. Results: In MPA-treated R+ KTR, both αβ and γδ T-cells displayed a more dysfunctional phenotype (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. In mTORi-treated patients (n= 27), the proportion of PD-1+ and CD85j+ αβ and γδ T cells decreased when compared to MPA-treated patients (n=44), as well as the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of latedifferentiated and cytotoxic γδ T cells, and IFNγ-producing and cytotoxic αβ T cells. In vitro, mTORi increased proliferation, viability, and CMV-induced IFNγ production of T cells and (decreased PD-1 and CD85j expression in T cells that shifted to a more efficient EOMESlow Hobithigh profile. In γδ T cells the mTORi effect was related to increased TCR signaling. Conclusion: Severe CMV replication is associated with a dysfunctional T-cell profile and mTORi improve T-cell fitness in association with better control of CMV. A dysfunctional Tcell phenotype could provide a new biomarker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment.