PDK1 Regulation of MTOR and Hypoxia-inducible Factor 1 Integrate Metabolism and Migration of CD8+ T Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2012 Nov 28

PMID 23183047

Citations 344

Authors

David K Finlay

Ella Rosenzweig

Linda V Sinclair

Carmen Feijoo-Carnero

Jens L Hukelmann

Julia Rolf

Andrey A Panteleyev

Klaus Okkenhaug

Doreen A Cantrell

Affiliations

Soon will be listed here.

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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References

Sinclair L, Finlay D, Feijoo C, Cornish G, Gray A, Ager A . Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Immunol. 2008; 9(5):513-21. PMC: 2857321. DOI: 10.1038/ni.1603. View

Larance M, Kirkwood K, Xirodimas D, Lundberg E, Uhlen M, Lamond A . Characterization of MRFAP1 turnover and interactions downstream of the NEDD8 pathway. Mol Cell Proteomics. 2011; 11(3):M111.014407. PMC: 3316733. DOI: 10.1074/mcp.M111.014407. View

Geng S, Mezentsev A, Kalachikov S, Raith K, Roop D, Panteleyev A . Targeted ablation of Arnt in mouse epidermis results in profound defects in desquamation and epidermal barrier function. J Cell Sci. 2006; 119(Pt 23):4901-12. DOI: 10.1242/jcs.03282. View

Waugh C, Sinclair L, Finlay D, Bayascas J, Cantrell D . Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation. Mol Cell Biol. 2009; 29(21):5952-62. PMC: 2772752. DOI: 10.1128/MCB.00585-09. View

Navarro M, Goebel J, Feijoo-Carnero C, Morrice N, Cantrell D . Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes. Nat Immunol. 2011; 12(4):352-61. PMC: 3110993. DOI: 10.1038/ni.2008. View

Shi L, Wang R, Huang G, Vogel P, Neale G, Green D . HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011; 208(7):1367-76. PMC: 3135370. DOI: 10.1084/jem.20110278. View

Huang D, Sherman B, Lempicki R . Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2008; 37(1):1-13. PMC: 2615629. DOI: 10.1093/nar/gkn923. View

Cham C, Gajewski T . Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J Immunol. 2005; 174(8):4670-7. DOI: 10.4049/jimmunol.174.8.4670. View

Powell J, Delgoffe G . The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity. 2010; 33(3):301-11. PMC: 2962404. DOI: 10.1016/j.immuni.2010.09.002. View

10.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

11.

Araki K, Turner A, Shaffer V, Gangappa S, Keller S, Bachmann M . mTOR regulates memory CD8 T-cell differentiation. Nature. 2009; 460(7251):108-12. PMC: 2710807. DOI: 10.1038/nature08155. View

12.

MacDonald H, Koch C . Energy metabolism and T-cell-mediated cytolysis. I. Synergism between inhibitors of respiration and glycolysis. J Exp Med. 1977; 146(3):698-709. PMC: 2180805. DOI: 10.1084/jem.146.3.698. View

13.

Cruz-Guilloty F, Pipkin M, Djuretic I, Levanon D, Lotem J, Lichtenheld M . Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med. 2009; 206(1):51-9. PMC: 2626671. DOI: 10.1084/jem.20081242. View

14.

Pircher H, Burki K, Lang R, Hengartner H, Zinkernagel R . Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature. 1989; 342(6249):559-61. DOI: 10.1038/342559a0. View

15.

Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S, Killeen N . Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity. 2010; 32(6):743-53. PMC: 2911434. DOI: 10.1016/j.immuni.2010.06.002. View

16.

MacIver N, Jacobs S, Wieman H, Wofford J, Coloff J, Rathmell J . Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J Leukoc Biol. 2008; 84(4):949-57. PMC: 2638731. DOI: 10.1189/jlb.0108024. View

17.

Brunn G, Williams J, Sabers C, Wiederrecht G, Lawrence Jr J, Abraham R . Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 1996; 15(19):5256-67. PMC: 452270. View

18.

Kerdiles Y, Beisner D, Tinoco R, Dejean A, Castrillon D, DePinho R . Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol. 2009; 10(2):176-84. PMC: 2856471. DOI: 10.1038/ni.1689. View

19.

Cox J, Mann M . MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008; 26(12):1367-72. DOI: 10.1038/nbt.1511. View

20.

Caldwell C, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov S . Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001; 167(11):6140-9. DOI: 10.4049/jimmunol.167.11.6140. View