PD-1 Alters T-cell Metabolic Reprogramming by Inhibiting Glycolysis and Promoting Lipolysis and Fatty Acid Oxidation

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Mar 27

PMID 25809635

Citations 621

Authors

Nikolaos Patsoukis

Kankana Bardhan

Pranam Chatterjee

Duygu Sari

Bianling Liu

Lauren N Bell

Edward D Karoly

Gordon J Freeman

Victoria Petkova

Pankaj Seth

Lequn Li

Vassiliki A Boussiotis

Affiliations

Soon will be listed here.

Abstract

During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated T cells are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty acid β-oxidation (FAO). PD-1 promotes FAO of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty acids. Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated cells. Because T cells utilize glycolysis during differentiation to effectors, our findings reveal a metabolic mechanism responsible for PD-1-mediated blockade of T-effector cell differentiation. The enhancement of FAO provides a mechanistic explanation for the longevity of T cells receiving PD-1 signals in patients with chronic infections and cancer, and for their capacity to be reinvigorated by PD-1 blockade.

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References

Schoenborn V, Heid I, Vollmert C, Lingenhel A, Adams T, Hopkins P . The ATGL gene is associated with free fatty acids, triglycerides, and type 2 diabetes. Diabetes. 2006; 55(5):1270-5. DOI: 10.2337/db05-1498. View

Warburg O . On respiratory impairment in cancer cells. Science. 1956; 124(3215):269-70. View

Duncan R, Wang Y, Ahmadian M, Lu J, Sarkadi-Nagy E, Sul H . Characterization of desnutrin functional domains: critical residues for triacylglycerol hydrolysis in cultured cells. J Lipid Res. 2009; 51(2):309-17. PMC: 2803232. DOI: 10.1194/jlr.M000729. View

St-Pierre J, Drori S, Uldry M, Silvaggi J, Rhee J, Jager S . Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006; 127(2):397-408. DOI: 10.1016/j.cell.2006.09.024. View

Zaugg K, Yao Y, Reilly P, Kannan K, Kiarash R, Mason J . Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 2011; 25(10):1041-51. PMC: 3093120. DOI: 10.1101/gad.1987211. View

Jenkins C, Mancuso D, Yan W, Sims H, Gibson B, Gross R . Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem. 2004; 279(47):48968-75. DOI: 10.1074/jbc.M407841200. View

Newsholme P, Curi R, Pithon Curi T, Murphy C, Garcia C, Pires de Melo M . Glutamine metabolism by lymphocytes, macrophages, and neutrophils: its importance in health and disease. J Nutr Biochem. 2004; 10(6):316-24. DOI: 10.1016/s0955-2863(99)00022-4. View

Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis V . Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 2012; 5(230):ra46. PMC: 5498435. DOI: 10.1126/scisignal.2002796. View

Egen J, Kuhns M, Allison J . CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002; 3(7):611-8. DOI: 10.1038/ni0702-611. View

10.

Villena J, Roy S, Sarkadi-Nagy E, Kim K, Sul H . Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. J Biol Chem. 2004; 279(45):47066-75. DOI: 10.1074/jbc.M403855200. View

11.

Marko A, Miller R, Kelman A, Frauwirth K . Induction of glucose metabolism in stimulated T lymphocytes is regulated by mitogen-activated protein kinase signaling. PLoS One. 2010; 5(11):e15425. PMC: 2978105. DOI: 10.1371/journal.pone.0015425. View

12.

Wieman H, Wofford J, Rathmell J . Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell. 2007; 18(4):1437-46. PMC: 1838986. DOI: 10.1091/mbc.e06-07-0593. View

13.

Reitman Z, Jin G, Karoly E, Spasojevic I, Yang J, Kinzler K . Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci U S A. 2011; 108(8):3270-5. PMC: 3044380. DOI: 10.1073/pnas.1019393108. View

14.

Shaikh S, Jolly C, Chapkin R . n-3 Polyunsaturated fatty acids exert immunomodulatory effects on lymphocytes by targeting plasma membrane molecular organization. Mol Aspects Med. 2011; 33(1):46-54. PMC: 3246093. DOI: 10.1016/j.mam.2011.10.002. View

15.

Wherry E . T cell exhaustion. Nat Immunol. 2011; 12(6):492-9. DOI: 10.1038/ni.2035. View

16.

van der Windt G, Everts B, Chang C, Curtis J, Freitas T, Amiel E . Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2011; 36(1):68-78. PMC: 3269311. DOI: 10.1016/j.immuni.2011.12.007. View

17.

Probst H, McCoy K, Okazaki T, Honjo T, van den Broek M . Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol. 2005; 6(3):280-6. DOI: 10.1038/ni1165. View

18.

Barata J, Silva A, Brandao J, Nadler L, Cardoso A, Boussiotis V . Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med. 2004; 200(5):659-69. PMC: 2212738. DOI: 10.1084/jem.20040789. View

19.

Francisco L, Sage P, Sharpe A . The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010; 236:219-42. PMC: 2919275. DOI: 10.1111/j.1600-065X.2010.00923.x. View

20.

Parry R, Chemnitz J, Frauwirth K, Lanfranco A, Braunstein I, Kobayashi S . CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005; 25(21):9543-53. PMC: 1265804. DOI: 10.1128/MCB.25.21.9543-9553.2005. View