Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis

• Published in: Nature communications 2022-12, Vol.13 (1), p.7404-7404, Article 7404
• Main Authors: Werlen, Guy, Li, Mei-Ling, Tottone, Luca, da Silva-Diz, Victoria, Su, Xiaoyang, Herranz, Daniel, Jacinto, Estela
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 38; 38/77; 49; 631/250/1619/554; 631/250/1619/554/1775; 631/80/86/2369; 96; 96/31; 96/47; 96/95; AKT protein; Animals; Biosynthesis; Cell lineage; Defects; Dietary supplements; Fetuses; Fructose-6-phosphate; Gene expression; Gene rearrangement; Glucosamine; Glutamine; Glycosylation; Hexosamines; Humanities and Social Sciences; Ketoglutaric acid; Lymphocytes; Lymphocytes T; Metabolites; Mice; multidisciplinary; N-glycans; Nutrients; Ontogeny; Phosphatidylinositol 3-Kinases; Polysaccharides; Protein folding; Receptors; Receptors, Antigen, T-Cell, gamma-delta; Science; Science (multidisciplinary); T cell receptors; Thymus
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35014-w

T cell development requires the coordinated rearrangement of T cell receptor (TCR) gene segments and the expression of either αβ or γδ TCR. However, whether and how de novo synthesis of nutrients contributes to thymocyte commitment to either lineage remains unclear. Here, we find that T cell-specific deficiency in glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of the de novo hexosamine biosynthesis pathway ( dn -HBP), attenuates hexosamine levels, blunts N -glycosylation of TCRβ chains, reduces surface expression of key developmental receptors, thus impairing αβ-T cell ontogeny. GFAT1 deficiency triggers defects in N -glycans, increases the unfolded protein response, and elevates  γδ-T cell numbers despite reducing γδ-TCR diversity. Enhancing TCR expression or PI3K/Akt signaling does not reverse developmental defects. Instead, dietary supplementation with the salvage metabolite, glucosamine, and an α-ketoglutarate analogue partially restores αβ-T cell development in GFAT1 T-/- mice, while fully rescuing it in ex vivo fetal thymic organ cultures. Thus, dn -HBP fulfils, while salvage nutrients partially satisfy, the elevated demand for hexosamines during early T cell development. Although T cell commitment to specific lineages coincides with the rearrangement of T cell receptor loci, it remains unclear whether metabolism also influences this process. Here, authors show that de novo hexosamine biosynthesis promotes  αβ T cell lineage commitment and γδ-TCR diversity and can be modulated by dietary supplementation.