SA-4-1BBL Costimulation Inhibits Conversion of Conventional CD4+ T Cells into CD4+FoxP3+ T Regulatory Cells by Production of IFN-γ 英文参考文献.docVIP

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SA-4-1BBL Costimulation Inhibits Conversion of Conventional CD4+ T Cells into CD4+FoxP3+ T Regulatory Cells by Production of IFN-γ 英文参考文献.doc

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SA-4-1BBLCostimulationInhibitsConversionofConventionalCD4TCellsintoCD4FoxP3TRegulatoryCellsbyProductionofIFN-γ英文参考文献

SA-4-1BBLCostimulationInhibitsConversionof ConventionalCD4 TCellsintoCD4 FoxP3+TRegulatory + + CellsbyProductionofIFN-c ShravanMadireddi,Rich-HenrySchabowsky,AbhishekK.Srivastava,RajeshK.Sharma,EsmaS.Yolcu*., HavalShirwan*. InstituteforCellularTherapeutics,DepartmentofMicrobiologyandImmunology,andJamesBrownCancerCenter,UniversityofLouisville,Louisville,Kentucky,United StatesofAmerica Abstract TumorsconvertconventionalCD4+TcellsintoinducedCD4+CD25+FoxP3+Tregulatory(iTreg)cellsthatserveasaneffective meansofimmuneevasion.Therefore,theblockadeofconventionalCD4 TcellconversionintoiTregcellsrepresentsan attractive target for improving the efficacy of various immunotherapeutic approaches. Using a novel form of 4-1BBL + + + molecule, SA-4-1BBL, we previously demonstrated that costimulation via 4-1BB receptor renders both CD4 and CD8 T effector(Teff)cellsrefractorytoinhibitionbyTregcellsandincreasedintratumoralTeff/Tregcellratiothatcorrelatedwith therapeuticefficacyinvariouspreclinicaltumormodels.Buildingonthesestudies,wehereinshowforthefirsttime,toour + knowledge,thatsignalingthrough4-1BBinhibitsantigen-andTGF-b-drivenconversionofna?¨veCD4 FoxP32Tcellsinto + iTregcellsviastimulationofIFN-cproductionbyCD4 FoxP32Tcells.Importantly,treatmentwithSA-4-1BBLblockedthe + conversionofCD4 FoxP32TcellsintoTregcellsbyEG.7tumors.Takentogetherwithourpreviousstudies,theseresults show that 4-1BB signaling negatively modulate Treg cells by two distinct mechanisms: i) inhibiting the conversion of + CD4 FoxP32TcellsintoiTregcellsandii)endowingTeffcellsrefractorytoinhibitionbyTregcells.Giventhedominantrole ofTregcellsintumorimmuneevasionmechanisms,4-1BBsignalingrepresentsanattractivetargetforfavorablytippingthe Teff:TregbalancetowardTeffcellswithimportantimplicationsforcancerimmunotherapy. Citation:MadireddiS,SchabowskyR-H,SrivastavaAK,SharmaRK,YolcuES,etal.(2012)SA-4-1BBLCostimulationInhibitsConversionofConventionalCD4+T CellsintoCD4 FoxP3+TRegulatoryCellsbyProductionofIF