The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not complet...The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not completely known.Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells,such as immune presenting cells or tumor cells.In this study,we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs,involving their TCR and the butyrophilins BTN3A1 and BTN2A1.This is the first time that these three molecules,concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells,have been shown to be involved together on the same and unique T cell during PAg activation.Moreover,the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed byγ9TCR,BTN3A1 and BTN2A1.The self-activation of Vγ9Vδ2 T cells,which leads to self-killing,can therefore participate in the failure ofγδT cell-based therapies with exogenous PAgs and should be taken into account.展开更多
During their life,T cells are constantly circulating throughout the body.Sphingosine-1-phosphate(S1P),a sphingolipid metabolite,triggers T cell egress from the thymus and secondary lymphoid organs(SLO)into the lymph a...During their life,T cells are constantly circulating throughout the body.Sphingosine-1-phosphate(S1P),a sphingolipid metabolite,triggers T cell egress from the thymus and secondary lymphoid organs(SLO)into the lymph and the blood.This phenomenon is dependent on the S1P gradient between lymphoid organs(including thymus and SLO)and the lymphatic and blood vessels,which exhibit low,intermediate and high S1P levels,respectively.T cells follow the S1P gradient via the engagement of the G-protein-coupled receptor S1P receptor 1(S1P1)expressed on T cells.1 S1P production is regulated by various sphingolipid-metabolizing enzymes.The sphingosine kinases 1 and 2(SKs),encoded by Sphk1 and Sphk2,phosphorylate the sphingosine(Sph)into S1P.Conversely,S1P can be dephosphorylated to Sph by S1P phosphatases 1 and 2,encoded by Sgpp1 and Sgpp2.Alternatively,S1P can be irreversibly degraded by the S1P Lyase(SPL),encoded by Sgpl1,into phosphoethanolamine and hexadecenal.展开更多
基金This work was funded by INSERM,CNRS,the University Hospital of Bordeaux,and Toulouse III University.We acknowledge ImCheck for providing the 103.2 antibody and the 7.48 antibody.We are grateful to our healthcare professionals for their boundless efforts during the COVID-19 crisis.
文摘The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not completely known.Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells,such as immune presenting cells or tumor cells.In this study,we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs,involving their TCR and the butyrophilins BTN3A1 and BTN2A1.This is the first time that these three molecules,concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells,have been shown to be involved together on the same and unique T cell during PAg activation.Moreover,the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed byγ9TCR,BTN3A1 and BTN2A1.The self-activation of Vγ9Vδ2 T cells,which leads to self-killing,can therefore participate in the failure ofγδT cell-based therapies with exogenous PAgs and should be taken into account.
文摘During their life,T cells are constantly circulating throughout the body.Sphingosine-1-phosphate(S1P),a sphingolipid metabolite,triggers T cell egress from the thymus and secondary lymphoid organs(SLO)into the lymph and the blood.This phenomenon is dependent on the S1P gradient between lymphoid organs(including thymus and SLO)and the lymphatic and blood vessels,which exhibit low,intermediate and high S1P levels,respectively.T cells follow the S1P gradient via the engagement of the G-protein-coupled receptor S1P receptor 1(S1P1)expressed on T cells.1 S1P production is regulated by various sphingolipid-metabolizing enzymes.The sphingosine kinases 1 and 2(SKs),encoded by Sphk1 and Sphk2,phosphorylate the sphingosine(Sph)into S1P.Conversely,S1P can be dephosphorylated to Sph by S1P phosphatases 1 and 2,encoded by Sgpp1 and Sgpp2.Alternatively,S1P can be irreversibly degraded by the S1P Lyase(SPL),encoded by Sgpl1,into phosphoethanolamine and hexadecenal.
