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

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

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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,including ß-selection,regulatory T-cell generation and γδT-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.

N-glycosylationT-cell developmentThymocytesGlycocalyxInflammation

Manuel M.Vicente、Inês Alves、?ngela 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、Salomé S.Pinho

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i3S-Institute for Research and Innovation in Health,University of Porto,Porto,Portugal

Institute of Biomedical Sciences Abel Salazar(ICBAS),University of Porto,Porto,Portugal

Graduate Program in Areas of Basic and Applied Biology(GABBA),ICBAS,University of Porto,Porto,Portugal

Faculty of Medicine,University of Porto,Porto,Portugal

Nephrology Department,Centro Hospitalar e Universitário do Porto,Porto,Portugal

Institute of Immunology,Hannover Medical School,Hannover,Germany

Institute of Clinical Biochemistry,Hannover Medical School,Hannover,Germany

Instituto de Medicina Molecular João Lobo Antunes,Faculdade de Medicina,Universidade de Lisboa,Lisboa,Portugal

Laboratorio de Inmunopatologia,Instituto de Biologia y Medicina Experimental(IBYME),Consejo Nacional de Investigaciones Cientificas y Tecnicas(CONICET),Ciudad de Buenos Aires,Argentina

Laboratorio de Inmuno-oncologia Translacional,Instituto de Biologia y Medicina Experimental(IBYME),Consejo Nacional de Investigaciones Cientificas y Tecnicas(CONICET),Ciudad de Buenos Aires,Argentina

Facultad de Ciencias Exactas y Naturales(FCEyN),Universidad de Buenos Aires,Ciudad de Buenos Aires,Argentina

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2022 Lupus Research Alliance(LRA)Lupus Innovation AwardInstitutional funding from the Portuguese Foundation for Science and Technology(FCT)Institutional funding from the Portuguese Foundation for Science and Technology(FCT)Institutional funding from the Portuguese Foundation for Science and Technology(FCT)Institutional funding from the Portuguese Foundation for Science and Technology(FCT)European Union(ERC Synergy,GlycanSwitch)European Union,GlycanTrigger projectA grant was received from the Portuguese group of study in autoimmune diseases(NEDAI)FCTFCT

NORTE-01-0145-FEDER-000029POCI-01/0145-FEDER-016601POCI-01-0145-FEDER-028772PTDC/MEC-REU/28772/20101071386101093997PD/BD/135452/2017COVID/BD/152488/2022

2023

10.1038/s41423-023-01052-7

中国免疫学杂志(英文版)
中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI
影响因子：0.731
ISSN：1672-7681
年,卷(期)：2023.20(8)
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