| First Author | Werlen G | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 7404 |
| PubMed ID | 36456551 | Mgi Jnum | J:335152 |
| Mgi Id | MGI:7397670 | Doi | 10.1038/s41467-022-35014-w |
| Citation | Werlen G, et al. (2022) Dietary glucosamine overcomes the defects in alphabeta-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis. Nat Commun 13(1):7404 |
| abstractText | T cell development requires the coordinated rearrangement of T cell receptor (TCR) gene segments and the expression of either alphabeta or gammadelta 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 TCRbeta chains, reduces surface expression of key developmental receptors, thus impairing alphabeta-T cell ontogeny. GFAT1 deficiency triggers defects in N-glycans, increases the unfolded protein response, and elevates gammadelta-T cell numbers despite reducing gammadelta-TCR diversity. Enhancing TCR expression or PI3K/Akt signaling does not reverse developmental defects. Instead, dietary supplementation with the salvage metabolite, glucosamine, and an alpha-ketoglutarate analogue partially restores alphabeta-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. |
