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

Abstract

The reported association of mTOR-inhibitor (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in kidney transplant recipients (KTR) who are CMV seropositive (R+) remains unexplained. The incidence of CMV infection and T-cell profile was compared between KTRs treated with mTORis and mycophenolic acid (MPA), and <i>in vitro</i> mTORi effects on T-cell phenotype and functions were analyzed. In KTRs who were R+ and treated with MPA, both <i>αβ</i> and <i>γδ</i> T cells displayed a more dysfunctional phenotype (PD-1+, CD85j+) at day 0 of transplantation in the 16 KTRs with severe CMV infection, as compared with the 17 KTRs without or with spontaneously resolving CMV infection. In patients treated with mTORis (<i>n</i>=27), the proportion of PD-1+ and CD85j+ <i>αβ</i> and <i>γδ</i> T cells decreased, when compared with patients treated with MPA (<i>n</i>=44), as did the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of late-differentiated and cytotoxic <i>γδ</i> T cells and IFN<i>γ</i>-producing and cytotoxic <i>αβ</i> T cells. <i>In vitro</i>, mTORis increased proliferation, viability, and CMV-induced IFN<i>γ</i> production of T cells and decreased PD-1 and CD85j expression in T cells, which shifted the T cells to a more efficient EOMES^low Hobit^high profile. In <i>γδ</i> T cells, the mTORi effect was related to increased TCR signaling. Severe CMV replication is associated with a dysfunctional T-cell profile and mTORis improve T-cell fitness along with better control of CMV. A dysfunctional T-cell phenotype could serve as a new biomarker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment. Proportion of CMV Seropositive Kidney Transplant Recipients Who Will Develop a CMV Infection When Treated With an Immunosuppressive Regimen Including Everolimus and Reduced Dose of Cyclosporine Versus an Immunosuppressive Regimen With Mycophenolic Acid and Standard Dose of Cyclosporine A (EVERCMV), NCT02328963.