HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

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作者：

LZ Shi，R Wang，G Huang，P Vogel，G Neale，DR Green，H Chi

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摘要：

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 T(H)17 and Foxp3-expressing regulatory T cells (T(reg) cells) and controls cell fate determination. T(H)17 but not T(reg) cell-inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited T(H)17 development while promoting T(reg) cell generation. Moreover, the transcription factor hypoxia-inducible factor 1± (HIF1±) was selectively expressed in T(H)17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1±-dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between T(H)17 and T(reg) cells. Lack of HIF1± resulted in diminished T(H)17 development but enhanced T(reg) cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1±-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T(H)17 and T(reg) cells.

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关键词：

Animals Mice, Inbred C57BL Mice, Knockout Mice Liver Microbodies Clofibrate Pyrimidines Transcription Factors RNA