Protection and Polyfunctional T Cells Induced by Ag85B-TB10.4IC31？ against Mycobacterium tuberculosis Is Highly Dependent on the Antigen Dose 英文参考文献.docVIP

ProtectionandPolyfunctionalTCellsInducedbyAg85B- TB10.4/IC31HagainstMycobacteriumtuberculosisIs HighlyDependentontheAntigenDose ClausAagaard1.,TrucThiKimThanhHoang1.,AngeloIzzo2,RolfBilleskov1,JoLynnTroudt2 ,Kim Arnett2,AndrewKeyser2,TaraElvang1,PeterAndersen1,JesDietrich1* 1DepartmentofInfectiousDiseaseImmunology,StatensSerumInstitute,Copenhagen,Denmark,2DepartmentofMicrobiology,ImmunologyandPathology,Colorado StateUniversity,FortCollins,Colorado,UnitedStatesofAmerica Abstract Background:PreviouslywehaveshownthatAg85B-TB10.4isahighlyefficientvaccineagainsttuberculosiswhendelivered inaTh1inducingadjuvantbasedoncationicliposomes.AnotherTh1inducingadjuvant,whichhasshownaverypromising profileinbothpreclinicalandclinicaltrials,isIC31H.Inthisstudy,weexaminedthepotentialofAg85B-TB10.4deliveredin theadjuvantIC31HfortheabilitytoinduceprotectionagainstinfectionwithMycobacteriumtuberculosis.Inaddition,we examinediftheantigendosecouldinfluencethephenotypeoftheinducedTcells. Methods and Findings: We found that vaccination with the combination of Ag85B-TB10.4 and IC31H resulted in high numbers of polyfunctional CD4 T cells co-expressing IL-2, IFN-c and TNF-a. This correlated with protection against subsequentchallengewithM.tbinthemouseTBmodel.Importantly,ourresultsalsoshowedthatboththevaccineinduced Tcellresponse,andtheprotectiveefficacy,washighlydependentontheantigendose.Thus,whereasantigendosesof5 and15mgdidnotinducesignificantprotectionagainstM.tb,reducingthedoseto0.5mgselectivelyincreasedthenumber ofpolyfunctionalTcellsandinducedastrongprotectionagainstinfectionwithM.tb.Theinfluenceofantigendosewasalso observed in the guinea pig model of aerosol infection with M.tb. In this model a 2.5 fold increase in the antigen dose reducedtheprotectionagainstinfectionwithM.tbtothelevelobservedinnon-vaccinatedanimals. Conclusions/Significance: Small changes in the antigen dose can greatly influence the induction of specific T cell subpopulationsandthedoseisthereforeacrucialfactorwhentes