N-glycans mannosylation controls T-cell development by reprogramming thymocyte commitment, fate and repertoire

T-cell development is a major physiological process occurring in complex organisms, that ensures the formation of T-cell receptors diverse repertoire, to recognize antigens throughout the life of the organism. The thymus offers a microenvironment for efficient development, where progenitor populations go through maturation steps, which, when not regulated, are associated with disease onset, including autoimmune disorders and cancer. Glycosylation is a major post-translational modification that occurs in virtually all cells, including T lymphocytes, regulating receptor-turnover, affinity and signaling. However, there is a missing knowledge on how glycans regulate lymphocyte development and their impact in T-cell functions. We discovered stage-specific glycosylation profiles in human and murine thymocyte populations. Thereafter, we generated two glycoengineered mouse models displaying N-glycosylation pathway deficiencies, at early DN stages, lacking the Mgat1 or Mgat2 genes. We demonstrated remarkable defects in key T-cell developmental stages, such as {beta}- and DP-selection, natural regulatory T-cell generation, {gamma}{delta} T development/differentiation and thymic egression, in Mgat1-deficient thymocytes, indicating a pathogenic role of mannose N-glycans in development. We also demonstrated that a single N-glycan antenna (modelled in Mgat2-deficient thymocytes) is sufficient to rescue key developmental processes. In conclusion, we demonstrated that mannosylated thymocytes render a dysregulation in T-cell development, associated with disease.