Metabolic plasticity of human T cells: Preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2-deoxy-glucose affects effector functions

European Journal of Immunology

Volumn 45, Issue 9, 2015, Pages 2504-2516

  Renner, Kathrin ^a,b   Geiselhöringer, Anna Lena ^a,b   Fante, Matthias ^a   Bruss, Christina ^a   Färber, Stephanie ^a,b   Schönhammer, Gabriele ^a,b   Peter, Katrin ^a   Singer, Katrin ^a   Andreesen, Reinhard ^a,b   Hoffmann, Petra ^a,b   Oefner, Peter ^a   Herr, Wolfgang ^a,b   Kreutz, Marina ^a,b  

^a UNIVERSITY HOSPITAL REGENSBURG   (Germany)

^b Regensburg Centre for Interventional Immunology (RCI)   (Germany)

Author keywords

2 deoxy glucose; ATP; Cytokines; Glucose deprivation; Human CD4 T cells; Human CD8 T cells; Metabolism; Mitochondrial inhibition

Indexed keywords

GAMMA INTERFERON; GLUCOSAMINE; INTERLEUKIN 10; INTERLEUKIN 2; INTERLEUKIN 4; TUMOR NECROSIS FACTOR; DEOXYGLUCOSE; GLUCOSE; IL4 PROTEIN, HUMAN; TUMOR NECROSIS FACTOR ALPHA;

ARTICLE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL RESPIRATION; CELL SIZE; CELL VIABILITY; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RELEASE; GLUCOSE METABOLISM; GLYCOLYSIS; HUMAN; HUMAN CELL; LYMPHOCYTE FUNCTION; LYMPHOCYTE PROLIFERATION; METABOLIC INHIBITION; MIXED LYMPHOCYTE REACTION; PLASTICITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; T LYMPHOCYTE SUBPOPULATION; BIOSYNTHESIS; CELL PROLIFERATION; CYTOLOGY; DEFICIENCY; DRUG EFFECTS; IMMUNOLOGY; METABOLISM; MITOCHONDRION; MONOCYTE; OXIDATIVE PHOSPHORYLATION; PRIMARY CELL CULTURE;

CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; CELL PROLIFERATION; DEOXYGLUCOSE; GLUCOSE; GLYCOLYSIS; HUMANS; INTERFERON-GAMMA; INTERLEUKIN-10; INTERLEUKIN-2; INTERLEUKIN-4; MITOCHONDRIA; MONOCYTES; OXIDATIVE PHOSPHORYLATION; PRIMARY CELL CULTURE; T-LYMPHOCYTE SUBSETS; TUMOR NECROSIS FACTOR-ALPHA;

EID: 84940955520     PISSN: 00142980     EISSN: 15214141     Source Type: Journal    
DOI: 10.1002/eji.201545473     Document Type: Article

References (36)

1. Finlay, D. and Cantrell, D. A., Metabolism, migration and memory in cytotoxic T cells. Nat. Rev. Immunol. 2011. 11: 109-117.
2. Pearce, E. L., Poffenberger, M. C., Chang, C. H. and Jones, R. G., Fueling immunity: insights into metabolism and lymphocyte function. Science 2013. 342: 1242454.
3. van der Windt, G. J. and Pearce, E. L., Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol. Rev. 2012. 249: 27-42.
4. Wang, R. and Green, D. R., Metabolic checkpoints in activated T cells. Nat. Immunol. 2012. 13: 907-915.
5. Marko, A. J., Miller, R. A., Kelman, A. and Frauwirth, K. A., Induction of glucose metabolism in stimulated T lymphocytes is regulated by mitogen-activated protein kinase signaling. PLoS One 2010. 5: e15425.
6. Cham, C. M. and Gajewski, T. F., Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J. Immunol. 2005. 174: 4670-4677.
7. Jacobs, S. R., Herman, C. E., Maciver, N. J., Wofford, J. A., Wieman, H. L., Hammen, J. J. and Rathmell, J. C., Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J. Immunol. 2008. 180: 4476-4486.
8. Wang, R., Dillon, C. P., Shi, L. Z., Milasta, S., Carter, R., Finkelstein, D., McCormick, L. L. et al., The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 2011. 35: 871-882.
9. Carr, E. L., Kelman, A., Wu, G. S., Gopaul, R., Senkevitch, E., Aghvanyan, A., Turay, A. M. et al., Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 2010. 185: 1037-1044.
10. Macintyre, A. N., Gerriets, V. A., Nichols, A. G., Michalek, R. D., Rudolph, M. C., Deoliveira, D., Anderson, S. M. et al., The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014. 20: 61-72.
11. Chang, C. H., Curtis, J. D., Maggi, L. B., Jr., Faubert, B., Villarino, A. V., O'Sullivan, D., Huang, S. C. et al., Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013. 153: 1239-1251.
12. Cao, Y., Rathmell, J. C. and Macintyre, A. N., Metabolic reprogramming towards aerobic glycolysis correlates with greater proliferative ability and resistance to metabolic inhibition in CD8 versus CD4 T cells. PLoS One 2014. 9: e104104.
13. MacDonald, H. R. and Cerottini, J. C., Inhibition of T cell-mediated cytolysis by 2-deoxy-D-glucose:dissociation of the inhibitory effect from glycoprotein synthesis. Eur. J. Immunol. 1979. 9: 466-470.
14. Chandramouli, V. and Carter, J. R., Jr., Metabolic effects of 2-deoxy-D-glucose in isolated fat cells. Biochim. Biophys. Acta 1977. 496: 278-291.
15. Sena, L. A., Li, S., Jairaman, A., Prakriya, M., Ezponda, T., Hildeman, D. A., Wang, C. R. et al., Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 2013. 38: 225-236.
16. Newsholme, E. A., Crabtree, B. and Ardawi, M. S., Glutamine metabolism in lymphocytes: its biochemical, physiological and clinical importance. Q. J. Exp. Physiol. 1985. 70: 473-489.
17. Frauwirth, K. A., Riley, J. L., Harris, M. H., Parry, R. V., Rathmell, J. C., Plas, D. R., Elstrom, R. L. et al., The CD28 signaling pathway regulates glucose metabolism. Immunity 2002. 16: 769-777.
18. Chang, W. K., Yang, K. D. and Shaio, M. F., Effect of glutamine on Th1 and Th2 cytokine responses of human peripheral blood mononuclear cells. Clin. Immunol. 1999. 93: 294-301.
19. Tripmacher, R., Gaber, T., Dziurla, R., Haupl, T., Erekul, K., Grutzkau, A., Tschirschmann, M. et al., Human CD4(+) T cells maintain specific functions even under conditions of extremely restricted ATP production. Eur. J. Immunol. 2008. 38: 1631-1642.
20. Gubser, P. M., Bantug, G. R., Razik, L., Fischer, M., Dimeloe, S., Hoenger, G., Durovic, B. et al., Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 2013. 14: 1064-1072.
21. Altman, B. J. and Dang, C. V., Normal and cancer cell metabolism: lymphocytes and lymphoma. FEBS J. 2012. 279: 2598-2609.
22. Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pages, C., Tosolini, M. et al., Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006. 313: 1960-1964.
23. Gerriets, V. A., Kishton, R. J., Nichols, A. G., Macintyre, A. N., Inoue, M., Ilkayeva, O., Winter, P. S. et al., Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 2015. 125: 194-207.
24. Finlay, D. K., Rosenzweig, E., Sinclair, L. V., Feijoo-Carnero, C., Hukelmann, J. L., Rolf, J., Panteleyev, A. A. et al., PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 2012. 209: 2441-2453.
25. Dziurla, R., Gaber, T., Fangradt, M., Hahne, M., Tripmacher, R., Kolar, P., Spies, C. M. et al., Effects of hypoxia and/or lack of glucose on cellular energy metabolism and cytokine production in stimulated human CD4+ T lymphocytes. Immunol. Lett. 2010. 131: 97-105.
26. Gatza, E., Wahl, D. R., Opipari, A. W., Sundberg, T. B., Reddy, P., Liu, C., Glick, G. D. et al., Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Sci. Transl. Med. 2011. 3: 67ra68.
27. Kuhnke, A., Burmester, G. R., Krauss, S. and Buttgereit, F., Bioenergetics of immune cells to assess rheumatic disease activity and efficacy of glucocorticoid treatment. Annal. Rheumatic Dis. 2003. 62: 133-139.
28. Eberhart, K., Renner, K., Ritter, I., Kastenberger, M., Singer, K., Hellerbrand, C., Kreutz, M. et al., Low doses of 2-deoxy-glucose sensitize acute lymphoblastic leukemia cells to glucocorticoid-induced apoptosis. Leukemia 2009. 23: 2167-2170.
29. Gottlob, K., Majewski, N., Kennedy, S., Kandel, E., Robey, R. B. and Hay, N., Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 2001. 15: 1406-1418.
30. MacDonald, H. R. and Koch, C. J., Energy metabolism and T-cell-mediated cytolysis. I. Synergism between inhibitors of respiration and glycolysis. J. Exp. Med. 1977. 146: 698-709.
31. Sukumar, M., Liu, J., Ji, Y., Subramanian, M., Crompton, J. G., Yu, Z., Roychoudhuri, R. et al., Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest. 2013. 123: 4479-4488.
32. Murray, C. M., Hutchinson, R., Bantick, J. R., Belfield, G. P., Benjamin, A. D., Brazma, D., Bundick, R. V. et al., Monocarboxylate transporter MCT1 is a target for immunosuppression. Nat. Chem. Biol. 2005. 1: 371-376.
33. Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E. et al., Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007. 109: 3812-3819.
34. Doherty, J. R., Yang, C., Scott, K. E., Cameron, M. D., Fallahi, M., Li, W., Hall, M. A. et al., Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis. Cancer Res. 2014. 74: 908-920.
35. Marchiq, I., Le Floch, R., Roux, D., Simon, M. P. and Pouyssegur, J., Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin. Cancer Res. 2015. 75: 171-180.
36. Bergmeier, H. U., Methoden der enzymatischen Analyse. Akademie Verlag, Berlin: 1970.