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

Author

Listed:
  • Guy Werlen

    (The State Univ. of New Jersey)

  • Mei-Ling Li

    (The State Univ. of New Jersey)

  • Luca Tottone

    (The State Univ. of New Jersey
    University of Miami Miller School of Medicine)

  • Victoria da Silva-Diz

    (The State Univ. of New Jersey)

  • Xiaoyang Su

    (The State Univ. of New Jersey)

  • Daniel Herranz

    (The State Univ. of New Jersey)

  • Estela Jacinto

    (The State Univ. of New Jersey)

Abstract

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 GFAT1T-/- 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.

Suggested Citation

  • Guy Werlen & Mei-Ling Li & Luca Tottone & Victoria da Silva-Diz & Xiaoyang Su & Daniel Herranz & Estela Jacinto, 2022. "Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35014-w
    DOI: 10.1038/s41467-022-35014-w
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    References listed on IDEAS

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    1. Guy Werlen & Barbara Hausmann & Ed Palmer, 2000. "A motif in the αβ T-cell receptor controls positive selection by modulating ERK activity," Nature, Nature, vol. 406(6794), pages 422-426, July.
    2. Haik Mkhikian & Ani Grigorian & Carey F. Li & Hung-Lin Chen & Barbara Newton & Raymond W. Zhou & Christine Beeton & Sevan Torossian & Gevork Grikor Tatarian & Sung-Uk Lee & Ken Lau & Erin Walker & Kat, 2011. "Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis," Nature Communications, Nature, vol. 2(1), pages 1-13, September.
    3. Michael Demetriou & Maria Granovsky & Sue Quaggin & James W. Dennis, 2001. "Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation," Nature, Nature, vol. 409(6821), pages 733-739, February.
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