Menu

A+ A A-

Download article

DOI: https://doi.org/10.22263/2312-4156.2018.5.7

Sheibak V.M., Pauliukavets A.Y.
Biochemical heterogeneity of T-lymphocytes
Grodno State Medical University, Grodno, Republic of Belarus

Vestnik VGMU. 2018;17(6):7-17.

Abstract.
After the activation lymphocytes pass to a state of high biochemical activity, mainly reprogramming the ATP production from oxidative phosphorylation to aerobic glycolysis. The increased glucose metabolism in activated T-lymphocytes requires coordinating a variety of enzyme transcription programs to simultaneously increase glycolysis rates, glutaminolysis, lipid synthesis and cholesterol synthesis at the same time preventing lipid oxidation and sterol outflow. Regulation and switching of metabolic pathways in T-lymphocytes are associated with proliferation and differentiation processes, which are controlled by both transcriptional and post-transcriptional mechanisms, and determine both metabolism and the function / differentiation of T-lymphocytes. In addition, the metabolic status of the organism as a whole (nutrients supply, stress) can affect the metabolism of lymphocytes changing their functional activity. The study of the influence of metabolic regulation, the role of the microenvironment, the supply of substrates for the functional activity of T-lymphocytes promotes the revealing of new approaches in the therapy of the immune systempathology.
Key words: T-lymphocytes, metabolism, aerobic glycolysis, regulation of T-lymphocytes metabolism.

References

1. Swainson L, Kinet S, Manel N, Battini JL, Sitbon M, Taylor N. Glucose transporter 1 expression identifies a population of cycling CD4+ CD8+ human thymocytes with high CXCR4-induced chemotaxis. Proc Natl Acad Sci U S A. 2005 Sep;102(36):12867-72. doi: http://dx.doi.org/10.1073/pnas.0503603102
2. Warburg O, Gawehn K, Geissler AW. Metabolism of leukocytes. Z Naturforsch B. 1958 Aug;13B(8):515-6.
3. Fox CJ, Hammerman PS, Thompson CB. Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol. 2005 Nov;5(11):844-52. doi: http://dx.doi.org/10.1038/nri1710
4. Yu Q, Erman B, Bhandoola A, Sharrow SO, Singer A. In vitro evidence that cytokine receptor signals are required for differentiation of double positive thymocytes into functionally mature CD8+ T cells. J Exp Med. 2003 Feb;197(4):475-87.
5. Barata JT, Silva A, Brandao JG, Nadler LM, Cardoso AA, Boussiotis VA. 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 Sep;200(5):659-69. doi: http://dx.doi.org/10.1084/jem.20040789
6. Jacobs SR, Michalek RD, Rathmell JC. IL-7 is essential for homeostatic control of T cell metabolism in vivo. J Immunol. 2010 Apr;184(7):3461-9. doi: http://dx.doi.org/10.4049/jimmunol.0902593
7. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, et al. Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011 Mar;186(6):3299-303. doi: http://dx.doi.org/10.4049/jimmunol.1003613  
8. Sheybak VM, Pavlyukovets AYu. Metabolic activity of lymphocytes in the administration of biologically active substances and xenobiotics. Immunopatologiia Allergologiia Infektologiia. 2012;(4):37-43. (In Russ.)
9. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May;324(5930):1029-33. doi: http://dx.doi.org/10.1126/science.1160809
10. Bental M, Deutsch C. Metabolic changes in activated T cells: an NMR study of human peripheral blood lymphocytes. Magn Reson Med. 1993 Mar;29(3):317-26.
11. Macintyre AN, Rathmell JC Activated lymphocytes as a metabolic model for carcinogenesis. Cancer Metab. 2013 Jan;1(1):5. doi: http://dx.doi.org/10.1186/2049-3002-1-5
12. Michalek RD, Rathmell JC. The metabolic life and times of a T-cell. Immunol Rev. 2010 Jul;236:190-202. doi: http://dx.doi.org/10.1111/j.1600-065X.2010.00911.x
13. Jameson SC. Maintaining the norm: T-cell homeostasis. Nat Rev Immunol. 2002 Aug;2(8):547-56.
14. Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL, Hammen JJ, et al. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol. 2008 Apr;180(7):4476-86.
15. Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL, Hammen JJ, Anergic T cells are metabolically anergic. J Immunol. 2009 Nov;183(10):6095-101. doi: http://dx.doi.org/10.4049/jimmunol.0803510
16. Zheng Y, Collins SL, Lutz MA, Allen AN, Kole TP, Zarek PE, et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol. 2007 Feb;178(4):2163-70.
17. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011 Jul;208(7):1367-76. doi: http://dx.doi.org/10.1084/jem.20110278
18. Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D, Lui KO, et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci U S A. 2009 Jul;106(29):12055-60. doi: http://dx.doi.org/10.1073/pnas.0903919106
19. He S, Kato K, Jiang J, Wahl DR, Mineishi S, Fisher EM, et al. Characterization of the metabolic phenotype of rapamycin-treated CD8+ T cells with augmented ability to generate long-lasting memory cells. PLoS One. 2011;6(5):e20107. doi: http://dx.doi.org/10.1371/journal.pone.0020107
20. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012 Jan;36(1):68-78. doi: http://dx.doi.org/10.1016/j.immuni.2011.12.007
21. Gerriets VA, Rathmell JC. Metabolic pathways in T cell fate and function. Trends Immunol. 2012 Apr;33(4):168-73. doi: http://dx.doi.org/10.1016/j.it.2012.01.010
22. Ciofani M, Zuniga-Pflucker JC. Notch promotes survival of pre-T cells at the β-selection checkpoint by regulating cellular metabolism. Nat Immunol. 2005 Sep;6(9):881-8.
23. Rathmell JC, Vander Heiden MG, Harris MH, Frauwirth KA, Thompson CB. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol Cell. 2000 Sep;6(3):683-92.
24. Pearson C, Silva A, Seddon B. Exogenous amino acids are essential for interleukin-7 induced CD8 T cell growth. PLoS One. 2012;7(4):e33998. doi: http://dx.doi.org/10.1371/journal.pone.0033998
25. Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T cell survival. Blood. 2008 Feb;111(4):2101-11.
26. Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009 Nov;15(21):6479-83. doi: http://dx.doi.org/10.1158/1078-0432.CCR-09-0889
27. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009 Apr;458(7239):762-5. doi: http://dx.doi.org/10.1038/nature07823
28. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011 Dec;35(6):871-82. doi: http://dx.doi.org/10.1016/j.immuni.2011.09.021
29. Colombo SL, Palacios-Callender M, Frakich N, De Leon J, Schmitt CA, Boorn L, et al. Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes. Proc Natl Acad Sci U S A. 2010 Nov;107(44):18868-73. doi: http://dx.doi.org/10.1073/pnas.1012362107
30. Bensinger SJ, Bradley MN,  Joseph SB, Zelcer N, Janssen EM, Hausner MA, et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008 Jul;134(1):97-111. doi: http://dx.doi.org/10.1016/j.cell.2008.04.052
31. Edinger AL. Controlling cell growth and survival through regulated nutrient transporter expression. Biochem J. 2007 Aug;406(1):1-12. doi: http://dx.doi.org/10.1042/BJ20070490
32. Zhou QL, Jiang ZY, Holik J, Chawla A, Hagan GN, Leszyk J, et al. Akt substrate TBC1D1 regulates GLUT1 expression through the mTOR pathway in 3T3-L1 adipocytes. Biochem J. 2008 May;411(3):647-55. doi: http://dx.doi.org/10.1042/BJ20071084
33. Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via phosphatideylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell. 2007 Apr;18(4):1437-46.
34. Wieman HL, Horn SR, Jacobs SR, Altman BJ, Kornbluth S, Rathmell JC. An essential role for the Glut1 PDZ-binding motif in growth factor regulation of Glut1 degradation and trafficking. Biochem J. 2009 Mar;418(2):345-67. doi: http://dx.doi.org/10.1042/BJ20081422
35. Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 2008 Mar;15(3):521-9.
36. John S, Weiss JN, Ribalet B. Subcellular localization of hexokinases I and II directs the metabolic fate of glucose. PLoS One. 2011 Mar;6(3):e17674. doi: http://dx.doi.org/10.1371/journal.pone.0017674
37. Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol. 2012 Apr; 12(5):325-38.
38. Tandon P, Gallo CA, Khatri S, Barger JF, Yepiskoposyan H, Plas DR. Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency. Proc Natl Acad Sci U S A. 2011 Feb;108(6):2361-5. doi: http://dx.doi.org/10.1073/pnas.1013629108
39. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008 Sep;8(3):224-36. doi: http://dx.doi.org/10.1016/j.cmet.2008.07.007
40. Deberardinis RJ, Lum JJ, Thompson CB. Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. J Biol Chem. 2006 Dec;281(49):37372-80. doi: http://dx.doi.org/10.1074/jbc.M608372200
41. Powell JD, Delgoffe GM. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity. 2010 Sep;33(3):301-11. doi: http://dx.doi.org/10.1016/j.immuni.2010.09.002
42. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007 Oct;8(10):774-85. doi: http://dx.doi.org/10.1038/nrm2249
43. Tamás P, Hawley SA, Clarke RG, Mustard KJ, Green K, Hardie DG, et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med. 2006 Jul;203(7):1665-70. doi: http://dx.doi.org/10.1084/jem.20052469
44. Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998 Jan;18(1):38-43. doi: http://dx.doi.org/10.1038/ng0198-38
45. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A. 2004 Mar;101(10):3329-35.
46. Cao Y, Li H, Liu H, Zheng C, Ji H, Liu X. The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression. Cell Res. 2010 Jan;20(1):99-108. doi: http://dx.doi.org/10.1038/cr.2009.141
47. Tamás P, Macintyre A,  Finlay D, Clarke R, Feijoo-Carnero C, Ashworth A, et al. LKB1 is essential for the proliferation of T-cell progenitors and mature peripheral T cells. Eur J Immunol. 2010 Jan;40(1):242-53. doi: http://dx.doi.org/10.1002/eji.200939677
48. MacIver NJ, Blagih J, Saucillo DC, Tonelli L, Griss T, Rathmell JC, et al. The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J Immunol. 2011 Oct;187(8):4187-98. doi: http://dx.doi.org/10.4049/jimmunol.1100367
49. Alers S, Löffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012 Jan;32(1):2-11. doi: http://dx.doi.org/10.1128/MCB.06159-11
50. Hubbard VM, Valdor R, Patel B, Singh R, Cuervo AM, Macian F. Macroautophagy regulates energy metabolism during effector T cell activation J Immunol. 2010 Dec;185(12):7349-57. doi: http://dx.doi.org/10.4049/jimmunol.1000576

Information about authors:
Sheibak V.M. – Doctor of Medical Sciences, professor of the Chair of Biologic Chemistry, Grodno State Medical University;
Pauliukavets A.Y. – Candidate of Biological Sciences, associate professor of the Chair of Microbiology, Virology and Immunology named after S.I. Gelberg, Grodno State Medical University.

Correspondence address: Republic of Belarus, 230009, Grodno, 80, Gorky str., Grodno State Medical University, Chair of Microbiology, Virology and Immunology named after S.I. Gelberg. E-mail: Этот адрес электронной почты защищён от спам-ботов. У вас должен быть включен JavaScript для просмотра. – Anastasiya Y. Pauliukavets.

Поиск по сайту