Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 209, Issue 13, Pages 2441-2453Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20112607
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Funding
- Wellcome Trust [065975/Z/01/A]
- Wellcome Trust [065975/Z/01/A] Funding Source: Wellcome Trust
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mTORC1 (mammalian target of rapamycin complex 1) controls transcriptional programs that determine CD8(+) cytolytic T cell (CTL) fate. In some cell systems, mTORC1 couples phosphatidylinositol-3 kinase (PI3K) and Akt to the control of glucose uptake and glycolysis. However, PI3K-Akt-independent mechanisms control glucose metabolism in CD8(+) T cells, and the role of mTORC1 has not been explored. The present study now demonstrates that mTORC1 activity in CD8(+) T cells is not dependent on PI3K or Akt but is critical to sustain glucose uptake and glycolysis in CD8(+) T cells. We also show that PI3K- and Akt-independent pathways mediated by mTORC1 regulate the expression of HIF1 (hypoxia-inducible factor 1) transcription factor complex. This mTORC1-HIF1 pathway is required to sustain glucose metabolism and glycolysis in effector CTLs and strikingly functions to couple mTORC1 to a diverse transcriptional program that controls expression of glucose transporters, multiple rate-limiting glycolytic enzymes, cytolytic effector molecules, and essential chemokine and adhesion receptors that regulate T cell trafficking. These data reveal a fundamental mechanism linking nutrient and oxygen sensing to transcriptional control of CD8(+) T cell differentiation.
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