mTOR Inhibitors Prevent CMV Infection through the Restoration of Functional aβ and ?d T cells in Kidney Transplantation

Background 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 Methods The incidence of CMV infection and T-cell profile was compared between KTRs treated with mTORis and mycophenolic acid (MPA), and in vitro mTORi effects on T-cell phenotype and functions were analyzed. Results In KTRs who were R+ and treated with MPA, both a beta and ?d T cells displayed a more dysfunc-tional 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 (n=27), the proportion of PD-1+ and CD85j+ a beta and ?d T cells decreased, when compared with patients treated with MPA (n=44), as did the frequency and severity of CMV infections. mTORi treat-ment also led to higher proportions of late-differentiated and cytotoxic ?d T cells and IFN?-producing and cytotoxic a beta T cells. In vitro, mTORis increased proliferation, viability, and CMV-induced IFN? production of T cells and decreased PD-1 and CD85j expression in T cells, which shifted the T cells to a more efficient EOMESlow Hobit(high) profile. In ?d T cells, the mTORi effect was related to increased TCR signaling. Conclusion 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 bio-marker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment.

Automated summary

mTOR inhibitors have been shown to enhance T cell function and reduce the incidence of CMV infection in kidney transplant recipients. This effect may be achieved by reducing the number of dysfunctional T cells.