RegulatoryTcellsimpedeacuteandlong-termimmunitytoblood-stagemalariathroughCTLA-4SamarchithP.Kurup1,NyamekyeObeng-Adjei2,ScottM.Anthony1,BoubacarTraore3,OgobaraK.Doumbo3,NoahS.Butler1,PeterD.Crompton2,andJohnT.Harty1,*1DeptofMicrobiology,UniversityofIowaCarverCollegeofMedicine,IowaCity,IA,USA2LaboratoryofImmunogenetics,NationalInstituteofAllergyandInfectiousDiseases,NationalInstitutesofHealth,Rockville,MD,USA3MalariaResearchandTrainingCentre,DepartmentofEpidemiologyofParasiticDiseases,InternationalCenterofExcellenceinResearch,UniversityofSciences,TechniqueandTechnologyofBamako,BamakoBPE.1805,MaliAbstractMalaria,causedbytheprotozoanPlasmodiumisadevastatingmosquito-bornedisease,thatputsnearlyhalftheworld’spopulationatrisk1.DespitemountingsubstantialTandBcellresponses,humansfailtoefficientlycontrolblood-stagemalariaordevelopsterilizingimmunitytoreinfections2.ThoughFoxp3+regulatoryTcells(Tregs)formapartoftheseresponses3–5,theirinfluenceremainsdisputed,andmodeofactionunknown.HereweshowthatTregs,whichexpandinbothhumansandrodentsduringblood-stagemalaria,interferewithconventionalThelper(Th)cellresponsesandtheFollicularThelper(Tfh)cell:Bcellpartnershipingerminalcenters,inacriticaltemporalwindowtoimpedeprotectiveimmunity,throughtheCytotoxicT-lymphocyte-Associatedprotein(CTLA)-4.TargetingTregsorCTLA-4withpreciselytimeddepletionorblockingenhancedimmuneresponses,acceleratedclearance,andgeneratedspecies-transcendingimmunitytoblood-stagemalariainmice.Ourstudyuncoversacriticalmechanismofimmunosuppressionassociatedwithblood-stagemalariathatdelaysparasiteclearanceandpreventsdevelopmentofpotentadaptiveimmunitytoreinfection.ThesedataalsorevealatemporallydiscreteandtherapeuticallyamenablefunctionalroleforTregsinlimitinganti-malarialimmunity.CD4Thelper(Th)cellsarevitaltothecontrolofmalariainhumansandtherodentmodelsofdisease6.FrequenciesofactivatedThcellsincreasedduringthecourseofmalariainmiceandhumans(Supplementaryfigures1C,2)andtheirdepletionafterestablishedinfectionresultedinuncont...
