MechanismsofallergicdiseasesTheeffectofregulatoryTcellsontolerancetoairborneallergensandallergenimmunotherapyPetraBacher,PhD,a,bandAlexanderScheffold,PhDaKiel,GermanyForkheadboxP3–positiveregulatoryT(Treg)cellsareessentialmediatorsoftoleranceagainstself-antigensandharmlessexogenousantigens.Tregcelldeficienciesresultinmultipleautoimmuneandallergicsyndromesinneonates.HowTregcellsaffectconventionalallergiesagainstaeroantigens,whicharerestrictedtoafewspecificproteinsreleasedfrominhaledparticles,remainscontroversial.Thehallmarksofantigen-specificlossoftoleranceareallergen-specificTH2cellsandIgE.However,difficultiesinidentifyingtherareallergen-specificTregcellshaveobscuredthecellularbasisoftolerancetoaeroallergens,whichisalsoamajorobstaclefortherationaldesignofnovelandmoreefficientallergen-specificimmunotherapies.Recenttechnologicalprogressallowingcharacterizationofallergen-specificeffectorsandTregcellswithminimalinvitromanipulationrevealedtheirdetailedcontributiontotolerance.ThedataidentifiedinhaledparticlesasimmunodominantTregcelltargetsinhealthyandallergicsubjects.Conversely,thesupposedimmunodominantmajorallergensbeingrapidlyreleasedfrominhaledparticlesapparentlydonotactivelyinducetolerancebutareignoredbytheimmunesystem.Here,thepartiallycontradictorydataonvariousallergen-specificT-celltypesinhealthysubjects,allergicpatients,andpatientsundergoingallergen-specificimmunotherapyarediscussedandintegratedintoonemodel,postulatingTregcell–dependentandTregcell–independentcheckpointsoftoleranceandallergydevelopment.(JAllergyClinImmunol2018;142:1697-709.)Keywords:Aeroantigen,forkheadboxP3,regulatoryTcell,toler-ance,allergy,ignoranceAllergicdiseasesarecharacterizedasinappropriateimmuneresponsesagainsttypicallyinnocuoussubstances,suchasfoodorinhaledparticles.1,2CD41THcellsplayacentralroleintheregulationofprotectiveversuspathogenicimmuneresponses.AllergiesareinitiatedbyalossofT-celltolerance,leadingtoaberrantdevelopmentofTH2responsesagainstotherwiseharmlessairborneantigens.TH2...
