PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells

DK Finlay, E Rosenzweig, LV Sinclair… - Journal of Experimental …, 2012 - rupress.org
DK Finlay, E Rosenzweig, LV Sinclair, C Feijoo-Carnero, JL Hukelmann, J Rolf…
Journal of Experimental Medicine, 2012rupress.org
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 …
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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