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

cellular & Molecular Immunology 2023年第8期20卷 955-968页

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 i3S–Institute for Research and Innovation in Health University of PortoPortoPortugal Institute of Biomedical Sciences Abel Salazar(ICBAS) University of PortoPortoPortugal Graduate Program in Areas of Basic and Applied Biology(GABBA) ICBASUniversity of PortoPortoPortugal Faculty of Medicine University of PortoPortoPortugal nephrology Department Centro Hospitalar e Universitário do PortoPortoPortugal Institute of Immunology Hannover Medical SchoolHannoverGermany Institute of Clinical Biochemistry Hannover Medical SchoolHannoverGermany Instituto de Medicina Molecular João Lobo Antunes Faculdade de MedicinaUniversidade de LisboaLisboaPortugal Laboratorio de Inmunopatología Instituto de Biología y Medicina Experimental(IBYME)Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)Ciudad de Buenos AiresArgentina Laboratorio de Inmuno-oncología translacional Instituto de Biología y Medicina Experimental(IBYME)Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)Ciudad de Buenos AiresArgentina Facultad de Ciencias Exactas y naturales(FCEyn) Universidad de Buenos AiresCiudad de Buenos AiresArgentina

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

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