Open AccessmTOR Inhibitors Prevent CMV Infection through the Restoration of Functional αβ and γδ T cells in Kidney Transplantation
Author(s) -
Hannah Kaminski,
Gabriel Marsères,
Nathalie Yared,
Marie-Julie Nokin,
Vincent Pitard,
Atika Zouine,
Isabelle Garrigue,
Séverine Loizon,
Myriam Capone,
Xavier Gauthereau,
Maria Mamani-Matsuda,
Roxane Coueron,
Raứl V. Durán,
Benoı̂t Pinson,
Isabelle Pellegrin,
Rodolphe Thiébaut,
Lionel Couzi,
Pierre Merville,
Julie DéchanetMerville
Publication year - 2022
Publication title -
journal of the american society of nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.451
H-Index - 279
eISSN - 1533-3450
pISSN - 1046-6673
DOI - 10.1681/asn.2020121753
Subject(s) - medicine , transplantation , cytomegalovirus , incidence (geometry) , kidney transplantation , mycophenolic acid , immunology , sirolimus , bk virus , t cell , gastroenterology , immune system , herpesviridae , virus , viral disease , physics , optics
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