Mannosylated glycans impair normal T-cell development by reprogramming commitment and repertoire diversity  

作　　者：Manuel M.Vicente Inês Alves Ângela Fernandes Ana M.Dias Beatriz Santos-Pereira Elena Pérez-Anton Sofia Santos Tao Yang Alexandra Correia Anja Münster-Kühnel Afonso R.M.Almeida Sarina Ravens Gabriel A.Rabinovich Manuel Vilanova Ana E.Sousa SaloméS.Pinho 

机构地区：[1]i3S–Institute for Research and Innovation in Health,University of Porto,Porto,Portugal [2]Institute of Biomedical Sciences Abel Salazar(ICBAS),University of Porto,Porto,Portugal [3]Graduate Program in Areas of Basic and Applied Biology(GABBA),ICBAS,University of Porto,Porto,Portugal [4]Faculty of Medicine,University of Porto,Porto,Portugal [5]Nephrology Department,Centro Hospitalar e Universitário do Porto,Porto,Portugal [6]Institute of Immunology,Hannover Medical School,Hannover,Germany [7]Institute of Clinical Biochemistry,Hannover Medical School,Hannover,Germany [8]Instituto de Medicina Molecular João Lobo Antunes,Faculdade de Medicina,Universidade de Lisboa,Lisboa,Portugal [9]Laboratorio de Inmunopatología,Instituto de Biología y Medicina Experimental(IBYME),Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET),Ciudad de Buenos Aires,Argentina [10]Laboratorio de Inmuno-oncología Translacional,Instituto de Biología y Medicina Experimental(IBYME),Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET),Ciudad de Buenos Aires,Argentina [11]Facultad de Ciencias Exactas y Naturales(FCEyN),Universidad de Buenos Aires,Ciudad de Buenos Aires,Argentina

出　　处：《Cellular & Molecular Immunology》2023年第8期955-968,共14页中国免疫学杂志（英文版）

基　　金：Funded by the“2022 Lupus Research Alliance(LRA)Lupus Innovation Award”.Institutional funding from the Portuguese Foundation for Science and Technology(FCT):projects NORTE-01-0145-FEDER-000029,POCI-01/0145-FEDER-016601,POCI-01-0145-FEDER-028772,and PTDC/MEC-REU/28772/2017(SSP);This study was co-funded by the European Union(ERC Synergy,GlycanSwitch,101071386);Views and opinions expressed are,however,those of the author(s)only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency.The study was also co-funded by the European Union,GlycanTrigger project,Grant Agreement No:101093997;Views and opinions expressed are,however,those of the author(s)only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency.Neither the European Union nor the granting authority can be held responsible for them.A grant was received from the Portuguese group of study in autoimmune diseases(NEDAI)to SSP.MMV(PD/BD/135452/2017,COVID/BD/152488/2022)received funding from the FCT.

摘　　要：T-cell development ensures the formation of diverse repertoires of T-cell receptors(TCRs)that recognize a variety of antigens.Glycosylation is a major posttranslational modification present in virtually all cells,including T-lymphocytes,that regulates activity/functions.Although these structures are known to be involved in TCR-selection in DP thymocytes,it is unclear how glycans regulate other thymic development processes and how they influence susceptibility to disease.Here,we discovered stage-specific glycome compositions during T-cell development in human and murine thymocytes,as well as dynamic alterations.After restricting the N-glycosylation profile of thymocytes to high-mannose structures,using specific glycoengineered mice(Rag1CreMgat1fl/fl),we showed remarkable defects in key developmental checkpoints,includingß-selection,regulatory T-cell generation andγδT-cell development,associated with increased susceptibility to colon and kidney inflammation and infection.We further demonstrated that a single N-glycan antenna(modeled in Rag1CreMgat2fl/fl mice)is the sine-qua-non condition to ensure normal development.In conclusion,we revealed that mannosylated thymocytes lead to a dysregulation in T-cell development that is associated with inflammation susceptibility.

关 键 词：N-glycosylation T-cell development THYMOCYTES GLYCOCALYX Inflammation 

分 类 号：R392[医药卫生—免疫学]