HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
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DOI：
10.1084/jem.20110278
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发表时间：
2011-07-04
期刊：
影响因子：
--
通讯作者：
Chi H
中科院分区：
文献类型：
--
作者：
Shi LZ;Wang R;Huang G;Vogel P;Neale G;Green DR;Chi H
mTOR诱导HIF1α是TH17和Treg细胞分化的代谢检查点。在抗原刺激下，T细胞的生物能量需求在静息状态下急剧增加。虽然糖酵解的代谢转换作用已被认为支持增加的合成代谢活性和促进T细胞生长和增殖，但细胞代谢是否控制T细胞谱系选择仍然知之甚少。我们报道糖酵解途径在炎性TH17和表达foxp3的调节性T细胞（Treg细胞）分化过程中受到积极调节，并控制细胞命运的决定。诱导TH17而非Treg细胞的条件导致糖酵解活性的强烈上调和糖酵解酶的诱导。阻断糖酵解抑制TH17的发育，同时促进Treg细胞的生成。此外，转录因子缺氧诱导因子1α (HIF1α)在TH17细胞中选择性表达，其诱导需要通过mTOR信号传导，mTOR是细胞代谢的中枢调节因子。hif α依赖的转录程序在介导糖酵解活性中很重要，从而有助于TH17和Treg细胞之间的谱系选择。缺乏HIF1α导致TH17发育减少，但增强Treg细胞分化并保护小鼠免受自身免疫性神经炎症。我们的研究表明，hif α依赖的糖酵解途径为TH17和Treg细胞的分化策划了一个代谢检查点。
HIF1α induction by mTOR represents a metabolic checkpoint for the differentiation of TH17 and Treg cells. Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg cells) and controls cell fate determination. TH17 but not Treg cell–inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1α–dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1α resulted in diminished TH17 development but enhanced Treg cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
32.4
作者：
Kang Z;Altuntas CZ;Gulen MF;Liu C;Giltiay N;Qin H;Liu L;Qian W;Ransohoff RM;Bergmann C;Stohlman S;Tuohy VK;Li X
通讯作者：
Li X
DOI：
10.1038/nri2607
发表时间：
2009-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Rius, Jordi;Guma, Monica;Karin, Michael
通讯作者：
Karin, Michael
影响因子：
5.4
作者：
Cham, Candace M.;Driessens, Gregory;O'Keefe, James P.;Gajewski, Thomas F.
通讯作者：
Gajewski, Thomas F.