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

Abstract

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 regulateother thymic development processes and how they influence susceptibility to disease. Here, we discovered stage-specific glycomecompositions during T-cell development in human and murine thymocytes, as well as dynamic alterations. After restricting the Nglycosylationprofile of thymocytes to high-mannose structures, using specific glycoengineered mice (Rag1CreMgat1fl/fl), we showedremarkable defects in key developmental checkpoints, including ß-selection, regulatory T-cell generation and γδT-celldevelopment, associated with increased susceptibility to colon and kidney inflammation and infection. We further demonstratedthat a single N-glycan antenna (modeled in Rag1CreMgat2fl/fl mice) is the sine-qua-non condition to ensure normal development. Inconclusion, we revealed that mannosylated thymocytes lead to a dysregulation in T-cell development that is associated withi nflammation susceptibility.