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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Hypoxia-Inducible Factor 1
Phosphatidylinositol 3-Kinase
T-Lymphocytes
Glucose
Glycolysis
Facilitative Glucose Transport Proteins
Chemokine Receptors
mechanistic target of rapamycin complex 1
Cell Differentiation
Transcription Factors
Oxygen
Food
Enzymes

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Finlay, David K. ; Rosenzweig, Ella ; Sinclair, Linda V. ; Feijoo-Carnero, Carmen ; Hukelmann, Jens L. ; Rolf, Julia ; Panteleyev, Andrey A. ; Okkenhaug, Klaus ; Cantrell, Doreen A. / PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8 T cells. In: Journal of Experimental Medicine. 2012 ; Vol. 209, No. 13. pp. 2441-2453.
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Finlay, DK, Rosenzweig, E, Sinclair, LV, Feijoo-Carnero, C, Hukelmann, JL, Rolf, J, Panteleyev, AA, Okkenhaug, K & Cantrell, DA 2012, 'PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8 T cells', Journal of Experimental Medicine, vol. 209, no. 13, pp. 2441-2453. https://doi.org/10.1084/jem.20112607

PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8 T cells. / Finlay, David K.; Rosenzweig, Ella; Sinclair, Linda V.; Feijoo-Carnero, Carmen; Hukelmann, Jens L.; Rolf, Julia; Panteleyev, Andrey A.; Okkenhaug, Klaus; Cantrell, Doreen A.

In: Journal of Experimental Medicine, Vol. 209, No. 13, 17.12.2012, p. 2441-2453.

Research output: Contribution to journalArticle

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AU - Hukelmann, Jens L.

AU - Rolf, Julia

AU - Panteleyev, Andrey A.

AU - Okkenhaug, Klaus

AU - Cantrell, Doreen A.

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