Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis.
Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis.
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DOI：
10.1038/s41467-022-35014-w
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发表时间：
2022-12-01
影响因子：
16.6
通讯作者：
Jacinto, Estela
中科院分区：
文献类型：
--
作者：
Werlen, Guy;Li, Mei-Ling;Tottone, Luca;da Silva-Diz, Victoria;Su, Xiaoyang;Herranz, Daniel;Jacinto, Estela
T细胞的发育需要T细胞受体（TCR）基因片段的协调重排以及αβ或γδ TCR的表达。然而，营养物质的从头合成是否以及如何促进胸腺细胞对这两种谱系的承诺仍不清楚。在这里，我们发现T细胞特异性缺乏谷氨酰胺：果糖-6-磷酸氨基转移酶1 (GFAT1)，这是新生己糖胺生物合成途径（dn-HBP）的限速酶，降低己糖胺水平，使TCRβ链的n糖基化钝化，减少关键发育受体的表面表达，从而损害αβ-T细胞的个体发生。GFAT1缺陷引发n -聚糖缺陷，增加未折叠蛋白反应，并增加γδ-T细胞数量，尽管降低了γδ-TCR多样性。增强TCR表达或PI3K/Akt信号传导不能逆转发育缺陷。相反，在GFAT1T-/-小鼠中，在饮食中补充代谢物、葡萄糖胺和α-酮戊二酸类似物部分恢复αβ-T细胞的发育，同时在体外胎儿胸腺器官培养中完全恢复αβ-T细胞的发育。因此，在早期T细胞发育过程中，dn-HBP满足了对己糖胺的高需求，而救助营养素部分满足了对己糖胺的高需求。尽管T细胞对特定谱系的承诺与T细胞受体位点的重排一致，但尚不清楚代谢是否也影响这一过程。本研究表明，从头合成己糖胺可促进αβ T细胞谱系承诺和γδ-TCR多样性，并可通过膳食补充进行调节。
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. 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.
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影响因子：
64.5
作者：
Dennis JW;Nabi IR;Demetriou M
通讯作者：
Demetriou M
影响因子：
32.4
作者：
Ciofani, Maria;Knowles, Gisele C.;Zuniga-Pflucker, Juan Carlos
通讯作者：
Zuniga-Pflucker, Juan Carlos
DOI：
10.1084/jem.20131540
发表时间：
2014-02-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Coffey F;Lee SY;Buus TB;Lauritsen JP;Wong GW;Joachims ML;Thompson LF;Zúñiga-Pflücker JC;Kappes DJ;Wiest DL
通讯作者：
Wiest DL
影响因子：
4.8
作者：
Grigorian, Ani;Lee, Sung-Uk;Demetriou, Michael
通讯作者：
Demetriou, Michael
影响因子：
4
作者：
Cantor, Joseph M.;Ginsberg, Mark H.
通讯作者：
Ginsberg, Mark H.