Cited by 596PI3K/AKT/mTOR signaling in cancerT-cell and B-cell ImmunologyCancer, Hypoxia, and Metabolism

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

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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.·2012·Journal of Experimental Medicine

DOI 10.1084/jem.20112607PMC PMC3526360

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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 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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Authors: Finlay, D. K., Rosenzweig, E., Sinclair, L. V., Feijoo-Carnero, C., Hukelmann, J. L., Rolf, J., Panteleyev, A. A., Okkenhaug, K., & Cantrell, D. A.
Affiliations: Trinity College Dublin (IE)
University of Dundee (GB)
Division of Cell Signalling and Immunology, College of Life Sciences 3 ; and 4
Babraham Institute (GB)
Corresponding author: Finlay, David K.
Cantrell, Doreen A.
ORCID: Finlay, David K.
Sinclair, Linda V.
Hukelmann, Jens L.
Panteleyev, Andrey A.
Okkenhaug, Klaus
Cantrell, Doreen A.
Venue: Journal of Experimental Medicine
Publisher: Rockefeller University Press
Published: 2012-11-26
Volume: 209
Issue: 13
Pages: 2441-2453
ISSN: 0022-1007 (ISSN-L)
1540-9538
DOI: 10.1084/jem.20112607
PMC: PMC3526360
OpenAlex: W2164164239
Cited by: 596
References: 35
Citations by year: 2026: 29 · 2025: 33 · 2024: 32 · 2023: 43 · 2022: 46 · 2021: 59 · 2020: 47 · 2019: 56 · 2018: 45 · 2017: 43 · 2016: 49 · 2015: 46 · 2014: 36 · 2013: 29 · 2012: 2
FWCI: 14.52
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Journal of Experimental Medicine (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (acceptedVersion, other-oa)
Arrow@dit (Dublin Institute of Technology) (acceptedVersion)
Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, cc-by-nc-sa)
Apollo (University of Cambridge) (submittedVersion, cc-by-nc-sa)
Apollo
Funders: University of Dundee
Wellcome Trust (097418/Z/11/Z, 095691, 065975, 097418)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords: mTORC1, CD8+ T cells, cytotoxic T lymphocytes, HIF-1, glucose metabolism, glycolysis, glucose uptake, T cell migration, T cell differentiation, nutrient sensing, oxygen sensing, glucose transporters, chemokine receptors, cell adhesion receptors
MeSH terms: Mechanistic Target of Rapamycin Complex 1, Animals, Cell Differentiation, Cell Movement, Gene Expression Regulation, Glucose, Glycolysis, Interleukin-2, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Proteins, Receptors, Antigen, T-Cell, Protein Serine-Threonine Kinases, CD8-Positive T-Lymphocytes, Chemokines, Receptors, Chemokine, Phosphatidylinositol 3-Kinases, Multiprotein Complexes, Proto-Oncogene Proteins c-akt, Mice, Aryl Hydrocarbon Receptor Nuclear Translocator, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases, 3-Phosphoinositide-Dependent Protein Kinases

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

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