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

• Autor(a) principal: Vicente, MM
• Data de Publicação: 2023
• Outros Autores: Alves, I, Fernandes, Â, Dias, AM, Santos-Pereira, B, Pérez-Anton, E, Santos, S, Yang, T, Correia, A, Münster-Kühnel, A, Almeida, ARM, Ravens, S, Rabinovich, GA, Vilanova, M, Sousa, AE, Pinho, SS
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://hdl.handle.net/10216/150377
• topic: Glycocalyx; Inflammation; N-glycosylation; T-cell development; Thymocytes

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.