mTOR Inhibitors Prevent CMV Infection through the Restoration of Functional αβ and γδ T cells in Kidney Transplantation
Authors: Kaminski Hannah , Marseres Gabriel , Yared Nathalie , Nokin Marie-Julie , Pitard Vincent , Zouine Atika , Garrigue Isabelle , Loizon Séverine , Capone Myriam , Gauthereau Xavier , Mamani-Matsuda Maria , Coueron Roxane , Durán Raúl V. , Pinson Benoît , Pellegrin Isabelle , Thiébaut Rodolphe , Couzi Lionel , Merville Pierre , Déchanet-Merville Julie 
Published: November 2021

Significance Statement
It has been reported that mTOR inhibitors (mTORis) are associated with a reduction in the incidence of cytomegalovirus (CMV) infection in organ transplant patients who are CMV seropositive (R+), but a mechanistic explanation has been lacking to date. This work showed that a dysfunctional T-cell phenotype (CD85j+ PD-1+) was associated with a higher risk of uncontrolled CMV infection after transplantation in patients who were R+, and that mTORis reduced CMV incidence and severity by reinvigorating αβ and γδ T-cell function. Dysfunctional T-cell phenotype could represent a new biomarker to predict post-transplantation infection in patients who are R+ and to stratify patients who should benefit from treatment with mTORis.

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 αβ and γδ 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 (n=27), the proportion of PD-1+ and CD85j+ αβ and γδ T cells decreased, when compared with patients treated with MPA (n=44), as did the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of late-differentiated and cytotoxic γδ T cells and IFNγ-producing and cytotoxic αβ T cells. In vitro, mTORis increased proliferation, viability, and CMV-induced IFNγ production of T cells and decreased PD-1 and CD85j expression in T cells, which shifted the T cells 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 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.

Clinical Trial registry name and registration number:
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