Antigen Recognition By Autoreactive Cd4+ Thymocytes Drives Homeostasis Of The Thymic Medulla.docVIP

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Antigen Recognition By Autoreactive Cd4+ Thymocytes Drives Homeostasis Of The Thymic Medulla.doc

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AntigenRecognitionByAutoreactiveCd4ThymocytesDrivesHomeostasisOfTheThymicMedulla

AntigenRecognitionbyAutoreactiveCD4+Thymocytes DrivesHomeostasisoftheThymicMedulla MagaliIrla1*¤a,LuciaGuerri2,JeanneGuenot1.,ArnauldSerge′1.¤b,OlivierLantz2,AdrianListon3, BeatA.Imhof1,EdPalmer4,WalterReith1* 1Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland, 2De′partement de Biologie des Tumeurs and Inserm U932, InstitutCurie,Paris,France,3AutoimmuneGeneticsLaboratory,VIBandUniversityofLeuven,Leuven,Belgium,4ExperimentalTransplantationImmunology,Department ofBiomedicine,UniversityHospital-Basel,Basel,Switzerland Abstract The thymic medulla is dedicated for purging the T-cell receptor (TCR) repertoire of self-reactive specificities. Medullary thymicepithelialcells(mTECs)playapivotalroleinthisprocessbecausetheyexpressnumerousperipheraltissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single-positive (SP) thymocytes, the mechanisms underlying this requirement are incompletely understood. We demonstrate here that conventional SP CD4+ thymocytes bearing autoreactive TCRs drive a homeostatic process that fine-tunes medullary plasticityinadultmicebygoverningtheexpansionandpatterningofthemedulla.Thisprocessexhibitsstrictdependence onTCR-reactivitywithself-antigensexpressedbymTECs,aswellasengagementoftheCD28-CD80/CD86costimulatoryaxis. These interactions induce the expression of lymphotoxin a in autoreactive CD4+ thymocytes and RANK in mTECs. LymphotoxininturndrivesmTECdevelopmentinsynergywithRANKLandCD40L.OurresultsshowthatAg-dependent + interactionsbetweenautoreactiveCD4 thymocytesandmTECsfine-tunehomeostasisofthemedullabycompletingthe signalingaxesimplicatedinmTECexpansionandmedullaryorganization. Citation:IrlaM,GuerriL,GuenotJ,Serge′ A,LantzO,etal.(2012)AntigenRecognitionbyAutoreactiveCD4+ ThymocytesDrivesHomeostasisoftheThymic Medulla.PLoSONE7(12):e52591.doi:10.1371/journal.pone.0052591 Editor:JoseAlberola-Ila,OklahomaMedicalResearchFoundation,Uni