Reply to: GOT1 constrains TH17 cell differentiation, while promoting iTreg cell differentiation

Reply to: GOT1 constrains TH17 cell differentiation, while promoting iTreg cell differentiation
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DOI：
10.1038/s41586-022-05603-2
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发表时间：
2023
期刊：
Nature
影响因子：
--
通讯作者：
Sheng Ding
Sheng Ding
中科院分区：
--
文献类型：
--
作者：
Tao Xu;Zhen Qin;Xiaohu Wang;Chen Dong;Edward M. Driggers;Sheng Ding

文献摘要

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Metabolites derived from glutamine control the cell fate between T helper 17 (TH17) and regulatory T (Treg) cells; in our previous study1, we showed that glutamine metabolism in differentiating TH17 cells resulted in the accumulation of 2-hydroxyglutarate (2-HG), which could further promote TH17 cell determination by antagonizing the cellular program of induced T regulatory (iTreg) cells through the hypermethylation of Foxp3 gene loci and silencing of Foxp3 gene expression. Flux analysis using [U-13C]glutamine in TH17 cell cultures showed that glutamine metabolism produced approximately 50% of the total amount of α-ketoglutaric acid (αKG) and 2-HG through a glutamate-dependent transamination reaction, and blockade of this process by (aminooxy)acetic acid (AOA)—a well-known chemical inhibitor of transaminases—significantly decreased αKG-derived 2-HG and, as a consequence, shifted the differentiation of TH17 cells to Treg cells1. Genetic knockdown of Got1, a transaminase with the highest expression in TH17 cells and that is known to catalyse the interconversion of glutamine + oxaloacetate (OAA) to aspartate + αKG, mimics the effect of AOA and reprogrammed the differentiation of TH17 cells to iTreg cells, both in vitro and in an experimental autoimmune encephalomyelitis (EAE) model. Our previous study therefore revealed a crucial role of glutamine metabolism in the determination of TH17 cell fate and associated autoimmune diseases. In the accompanying Comment, W. Xu et al.2 confirmed our findings that AOA reprograms TH17 cell differentiation towards iTreg cells by decreasing αKG, but they approached their study of the function of GOT1 in a different context and concluded that GOT1 may have a much broader function in metabolic reprogramming to constrain TH17 cell differentiation and promote iTreg cell differentiation.