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

David K. Finlay, Ella Rosenzweig, Linda V. Sinclair, Carmen Feijoo-Carnero, Jens L. Hukelmann, Julia Rolf, Andrey A. Panteleyev, Klaus Okkenhaug, Doreen A. Cantrell

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Abstract

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 glycoly-sis. 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 demon-strates 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.
Original languageEnglish
Pages (from-to)2441-2453
Number of pages13
JournalJournal of Experimental Medicine
Volume209
Issue number13
DOIs
Publication statusPublished - 17 Dec 2012

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    Finlay, D. K., Rosenzweig, E., Sinclair, L. V., Feijoo-Carnero, C., Hukelmann, J. L., Rolf, J., Panteleyev, A. A., Okkenhaug, K., & Cantrell, D. A. (2012). PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8 T cells. Journal of Experimental Medicine, 209(13), 2441-2453. https://doi.org/10.1084/jem.20112607