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

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

  • J Am Soc Nephrol. 2022 Jan;33(1):121-137. doi: 10.1681/ASN.2020121753.
Hannah Kaminski 1 2,  Gabriel Marseres 2,  Nathalie Yared 2,  Marie-Julie Nokin 3,  Vincent Pitard 1 4,  Atika Zouine 4,  Isabelle Garrigue 5,  Séverine Loizon 2,  Myriam Capone 2,  Xavier Gauthereau 6,  Maria Mamani-Matsuda 2,  Roxane Coueron 7,  Raúl V Durán 3,  Benoît Pinson 8 9,  Isabelle Pellegrin 10,  Rodolphe Thiébaut 7,  Lionel Couzi 1 2,  Pierre Merville 1 2,  Julie Déchanet-Merville 11
Affiliations

Affiliations

  • 1 Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France.
  • 2 ImmunoConcEpT, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5164, University of Bordeaux, Bordeaux, France.
  • 3 Actions for onCogenesis understanding and Target Identification in ONcology, Institut Europeen de chimie et de biologie, Institut National de la Santé et de la Recherche Médicale, U1218, University of Bordeaux, Pessac, France.
  • 4 Centre National de la Recherche Scientifique Unité Mixte de Service 3427, Institut National de la Santé et de la Recherche Médicale US 005, TransBioMed Core, Flow Cytometry Facility, University of Bordeaux, Bordeaux, France.
  • 5 Virology Department, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5234 and CHU Bordeaux, University of Bordeaux, Bordeaux, France.
  • 6 Centre National de la Recherche Scientifique Unité Mixte de Service 3427, Institut National de la Santé et de la Recherche Médicale US 005, TransBioMed Core, PCRq'UB, University of Bordeaux, Bordeaux, France.
  • 7 Institut National de la Santé et de la Recherche Médicale U1219 Bordeaux Population Health Research Center, Inria SISTM, University of Bordeaux, Bordeaux, France.
  • 8 Centre National de la Recherche Scientifique Unité Mixte de Service 3427, Institut National de la Santé et de la Recherche Médicale US 005, TransBioMed Core, Service Analyses Métaboliques, University of Bordeaux, Bordeaux, France.
  • 9 Centre National de la Recherche Scientifique, Institut de Biochimie et Genetique Cellulaire Unité Mixte de Recherche 5095, University of Bordeaux, Bordeaux, France.
  • 10 Laboratory of Immunology and Immunogenetics, Bordeaux University Hospital, Bordeaux, France.
  • 11 ImmunoConcEpT, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5164, University of Bordeaux, Bordeaux, France jdechanet@immuconcept.org.
PMID: 34725108 DOI: 10.1681/ASN.2020121753
Abstract

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.

Keywords

CMV; CMV-specific immunity; kidney transplantation; mTOR inhibitors.

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