TY - JOUR
T1 - PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8 T cells
AU - Finlay, David K.
AU - Rosenzweig, Ella
AU - Sinclair, Linda V.
AU - Feijoo-Carnero, Carmen
AU - Hukelmann, Jens L.
AU - Rolf, Julia
AU - Panteleyev, Andrey A.
AU - Okkenhaug, Klaus
AU - Cantrell, Doreen A.
N1 - Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2012/12/17
Y1 - 2012/12/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84871861969&partnerID=8YFLogxK
U2 - 10.1084/jem.20112607
DO - 10.1084/jem.20112607
M3 - Article
C2 - 23183047
AN - SCOPUS:84871861969
SN - 0022-1007
VL - 209
SP - 2441
EP - 2453
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 13
ER -