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Insights into the physiology of the gamma-delta T Physiologie des lymphocytes T gamma-delta dans l'interaction du cytomégalovirus avec son hôte immunodéprimé

Abstract : Cytomegalovirus is a major infectious cause of mortality and morbidity following transplantation and a better knowledge about the immune cells acting against CMV and about their response to immunosuppressive drugs would help to better manage this life threatening infection. We have previously demonstrated that the tissue-associated adaptive Vδ2neg γδ T-cells are key effectors responding to CMV and associated to recovery. We analyzed here the repertoire and functions of naive Vδ2neg γδ T-cells to know better their "innate" properties against CMV. Secondly, an additional Vγ9negVδ2pos subgroup with adaptive functions has been recently described in adults. We demonstrated that these Vγ9negVδ2pos T-cells are also components of the CMV immune response while presenting with distinct characteristics from Vδ2neg γδT-cells. Notably Vγ9negVδ2pos T-cells were the only γδ T-cell subset which expansion tightly correlated with the severity of CMV disease. Consequently, we identified a new player in the immune response against CMV and open interesting clinical perspectives for using Vγ9negVδ2pos T-cells as an immune marker for CMV disease severity in immunocompromised patients.Finally, we analyzed the effect of mTOR-inhibitors (mTORi), immunosuppressive drugs, on CMV-specific T cells. Indeed, mTORi are inexplicably associated with a lower incidence of CMV infection in seropositive (R+) kidney transplant recipients (KTR). We hypothesized that CMV reactivation in R+ patients could be due to dysfunctional T cells that might be improved by mTORi. First we showed that both alpha-beta and gamma-delta T cells displayed a more dysfunctional phenotype (LAG3+, TIM3+, PD-1+, CD85j+) at day 0 in the 16 R+ KTR with severe CMV reactivation when compared to the 17 with spontaneously resolving or without CMV reactivation. Second, treating patients with mTORi (n= 27) decreased the proportion of PD-1+ and CD85j+ alpha-beta and gamma-delta T cells when compared to mycophenolic acid (MPA) treated patients (n=44), which correlate with the frequency and severity of CMV infections. mTORi-treated patients also lead to higher proportions of late-differentiated and cytotoxic gamma-delta T cells and increased percentages of IFN-gamma producing and cytotoxic alpha-beta T cells. In vitro, mTORi increased proliferation, survival and CMV-induced IFN-gamma-production of alpha-beta and gamma-delta T cells. mTORi also decreased PD-1 and CD85j expression in both subsets and shifted to a more efficient EOMESlow Hobit high profile. In gamma-delta T cells mTORi effect was related to increased TCR signaling. Those results reveal (i) that severe CMV replication is associated with a dysfunctional T cell profile and (ii) that mTORi improve their fitness in association with a better control of CMV. Dysfunctional T cell phenotype could represent a new biomarker in R+ patients to predict post-transplantation infection and help to stratify patients who should benefit from mTORi treatment.
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Submitted on : Tuesday, February 2, 2021 - 12:26:13 PM
Last modification on : Wednesday, June 9, 2021 - 3:09:58 AM


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  • HAL Id : tel-03128595, version 1



Hannah Kaminski. Insights into the physiology of the gamma-delta T Physiologie des lymphocytes T gamma-delta dans l'interaction du cytomégalovirus avec son hôte immunodéprimé. Human health and pathology. Université de Bordeaux, 2020. English. ⟨NNT : 2020BORD0328⟩. ⟨tel-03128595⟩



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