Retinoic acid signaling acts as a rheostat to balance Treg function

作     者：Govindarajan Thangavelu Gabriela Andrejeva Sara Bolivar-Wagers Sujeong Jin Michael C.Zaiken Michael Loschi Ethan G.Aguilar Scott N.Furlan Chrysothemis C.Brown Yu-Chi Lee Cameron McDonald Hyman Colby J.Feser Angela Panoskaltsis-Mortari Keli L.Hippen Kelli P.MacDonald William J.Murphy Ivan Maillard Geoffrey R.Hill David H.Munn Robert Zeiser Leslie S.Kean Jeffrey C.Rathmell Hongbo Chi Randolph J.Noelle Bruce R.Blazar 

作者机构：Department of PediatricsCenter for ImmunologyUniversity of MinnesotaMinneapolisMNUSA Center for ImmunobiologyVanderbilt University Medical CenterNashville TNUSA Department of PediatricsUniversity of WashingtonSeattleWAUSA Fred Hutchinson Cancer Research CenterSeattleWAUSA Howard Hughes Medical Institute Immunology Programand Ludwig CenterSloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Department of Microbiology and Immunology.Geisel School of Medicine at DartmouthNorris Cotton Cancer CenterLebanonUSA Department of ImmunologyQueensland Institute of Medical Research(QIMR)Berghofer Medical Research Institute and School of MedicineUniversity of QueenslandBrisbaneQLDAustralia Departmentof DermatologySchool of MedicineUniversity of California DavisSacramentoCAUSA Division of Hematology/OncologyDepartment of MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPAUSA Georgia Cancer CenterAugusta UniversityAugustaGAUSA Department of HaematologyOncology and Stem Cell TransplantationFaculty of MedicineFreiburg University Medical CentreFreiburgGermany Boston Children's Hospital and the Dana-Farber Cancer InstituteBostonMAUSA Department of ImmunologySt.Jude Children's ResearchHospitalMemphisTNUSA 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2022年第19卷第7期

页      面：820-833页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 10[医学] 

基　　金：This work was supported by grants from the National Institutes of Health,National Institute of Allergy and Infectious Diseases P01 AI056299,R37 AI034495(BRB),and R01 AI091627(IM)and the National Heart,Lung,and Blood Institute R01 HL56067(BRB) This work was supported in part using the resources of the Center for Innovative Technology at Vanderbilt University.GT was supported by a Canadian Institutes of Health Research(CIHR)fellowship 

主　　题：Retinoic acid Tregulatory cells Autoimmunity Metabolism mTORC1 STAT5 

摘      要：Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory *** certain inflammatory conditions,Tregs can lose their lineage stability and *** studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and ***,it is unknown how RA receptor signaling in Tregs influences these processes in ***,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(DN)RARαin all T *** the fact that DNRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor ***,DNRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic *** function was observed when wild-type mice were treated with a pharmacologic pan-RAR ***,Treg-specific expression of DNRARαresulted in distinct phenotypes,such that a single allele of DNRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and *** loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARαand wild-type bone marrow maintained the enhanced suppressive *** mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA *** findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.