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• W4226367159 abstract "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 IFN γ -producing and cytotoxic αβ T cells. In vitro , mTORis increased proliferation, viability, and CMV-induced IFN γ 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 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" @default.
• W4226367159 created "2022-05-05" @default.
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• W4226367159 date "2022-01-01" @default.
• W4226367159 modified "2023-10-10" @default.
• W4226367159 title "mTOR Inhibitors Prevent CMV Infection through the Restoration of Functional αβ and γδ T cells in Kidney Transplantation" @default.
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• W4226367159 doi "https://doi.org/10.1681/asn.2020121753" @default.
• W4226367159 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34725108" @default.
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