Metabolic pathways in T cell activation and lineage differentiation

Seminars in Immunology

Volumn 28, Issue 5, 2016, Pages 514-524

  Almeida, Luís ^a   Lochner, Matthias ^a   Berod, Luciana ^a   Sparwasser, Tim ^a  

^a INSTITUTE OF INFECTION IMMUNOLOGY   (Germany)

Author keywords

ACC; AMPK; Fatty acid metabolism; Glycolysis; Metabolism; mTOR; T cells

Indexed keywords

ACETYL COENZYME A; GLUCOSE TRANSPORTER 1; GLUCOSE TRANSPORTER 3; GLYCERALDEHYDE 3 PHOSPHATE DEHYDROGENASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MAMMALIAN TARGET OF RAPAMYCIN; MYC PROTEIN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE; TRANSCRIPTION FACTOR FOXP3; FATTY ACID;

AEROBIC GLYCOLYSIS; ANTIGEN RECOGNITION; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL FUNCTION; CELL METABOLISM; CELLULAR DISTRIBUTION; CHOLESTEROL SYNTHESIS; CITRIC ACID CYCLE; CYTOTOXIC T LYMPHOCYTE; EFFECTOR CELL; FATTY ACID METABOLISM; FATTY ACID SYNTHESIS; HELPER CELL; HUMAN; LYMPHOCYTE DIFFERENTIATION; MEMORY T LYMPHOCYTE; MITOCHONDRIAL RESPIRATION; NONHUMAN; OXIDATIVE PHOSPHORYLATION; REVIEW; T LYMPHOCYTE ACTIVATION; TH17 CELL; ANIMAL; CELL DIFFERENTIATION; CYTOLOGY; ENERGY METABOLISM; GLYCOLYSIS; IMMUNOLOGICAL MEMORY; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; METABOLISM; MITOCHONDRION; PHENOTYPE; PHYSIOLOGY; SIGNAL TRANSDUCTION; T LYMPHOCYTE SUBPOPULATION;

ANIMALS; CELL DIFFERENTIATION; ENERGY METABOLISM; FATTY ACIDS; GLYCOLYSIS; HUMANS; IMMUNOLOGIC MEMORY; LYMPHOCYTE ACTIVATION; METABOLIC NETWORKS AND PATHWAYS; MITOCHONDRIA; PHENOTYPE; SIGNAL TRANSDUCTION; T-LYMPHOCYTE SUBSETS;

EID: 85003681016     PISSN: 10445323     EISSN: 10963618     Source Type: Journal    
DOI: 10.1016/j.smim.2016.10.009     Document Type: Review

References (141)

1. [1] Zhang, N., et al. The role of apoptosis in the development and function of T lymphocytes. Cell Res. 15:10 (2005), 749–769.
2. [2] Wang, R., Green, D.R., Metabolic checkpoints in activated T cells. Nat. Immunol. 13:10 (2012), 907–915.
3. [3] Schumacher, T.N., Gerlach, C., van Heijst, J.W., Mapping the life histories of T cells. Nat. Rev. Immunol. 10:9 (2010), 621–631.
4. [4] Lunt, S.Y., Vander Heiden, M.G., Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27 (2011), 441–464.
5. [5] Liberti, M.V., Locasale, J.W., The warburg effect: how does it benefit cancer cells?. Trends Biochem. Sci. 41:3 (2016), 211–218.
6. [6] Chang, C.H., et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:6 (2013), 1239–1251.
7. [7] Otto, A.M., Warburg effect(s)—a biographical sketch of Otto Warburg and his impacts on tumor metabolism. Cancer Metabol. 4:1 (2016), 1–8.
8. [8] Nicholls, D.G., Ferguson, S.J., 5 – respiratory chains. Bioenergetics, fourth edition, 2013, Academic Press, Boston, 91–157.
9. [9] Alberts, B., Johnson, A., Lewis, J., Molecular biology of the cell. The Mitochondrion, 4th edition, 2002, N.Y.G. Science.
10. [10] Lochner, M., Berod, L., Sparwasser, T., Fatty acid metabolism in the regulation of T cell function. Trends Immunol. 36:2 (2015), 81–91.
11. [11] Nelson, D.L., Lehninger, A.L., Cox, M.M., Lehninger Principles of Biochemistry. 2008, W.H Freeman, New York.
12. [12] Schluns, K.S., et al. Interleukin-7 mediates the homeostasis of naive and memory CD8T cells in vivo. Nat. Immunol. 1:5 (2000), 426–432.
13. [13] Vivien, L., Benoist, C., Mathis, D., T lymphocytes need IL-7 but not IL-4 or IL-6 to survive in vivo. Int. Immunol. 13:6 (2001), 763–768.
14. [14] van der Windt, G.J., Pearce, E.L., Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol. Rev. 249:1 (2012), 27–42.
15. [15] Wang, R., et al. The transcription factor myc controls metabolic reprogramming upon t lymphocyte activation. Immunity 35:6 (2011), 871–882.
16. [16] Frauwirth, K.A., et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16:6 (2002), 769–777.
17. [17] Sinclair, L.V., et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14:5 (2013), 500–508.
18. [18] Macintyre, A.N., et al. The glucose transporter Glut1 is selectively essential for CD4T cell activation and effector function. Cell Metab. 20:1 (2014), 61–72.
19. [19] Lane, A.N., Fan, T.W., Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 43:4 (2015), 2466–2485.
20. [20] Swamy, M., et al. Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat. Immunol. 17:6 (2016), 712–720.
21. [21] Jacobs, S.R., et al. Glucose uptake is limiting in t cell activation and requires CD28-Mediated akt-Dependent and independent pathways. J. Immunol. 180:7 (2008), 4476–4486.
22. [22] Hukelmann, J.L., et al. The cytotoxic T cell proteome and its shaping by mammalian Target of Rapamycin. Nat. Immunol. 17:1 (2016), 104–112.
23. [23] Marko, A.J., et al. Induction of glucose metabolism in stimulated t lymphocytes is regulated by mitogen-Activated protein kinase signaling. PLoS One, 5(11), 2010.
24. [24] Lee, J.W., et al. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp. Mol. Med. 36:1 (2004), 1–12.
25. [25] Shi, L.Z., et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208:7 (2011), 1367–1376.
26. [26] Finlay, D.K., et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8(+) T cells. J. Exp. Med. 209:13 (2012), 2441–2453.
27. [27] Babcock, J.T., et al. Mammalian target of rapamycin complex 1 (mTORC1) enhances bortezomib-induced death in tuberous sclerosis complex (TSC)-null cells by a c-MYC-dependent induction of the unfolded protein response. J. Biol. Chem. 288:22 (2013), 15687–15698.
28. [28] Hatziapostolou, M., Polytarchou, C., Iliopoulos, D., miRNAs link metabolic reprogramming to oncogenesis. Trends Endocrinol. Metab. 24:7 (2013), 361–373.
29. [29] Waickman, A.T., Powell, J.D., mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol. Rev. 249:1 (2012), 43–58.
30. [30] Chantranupong, L., et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165:1 (2016), 153–164.
31. [31] Chen, L., et al. Hydrogen peroxide inhibits mTOR signaling by activation of AMPKalpha leading to apoptosis of neuronal cells. Lab. Invest. 90:5 (2010), 762–773.
32. [32] Waickman, A.T., Powell, J.D., Mammalian target of rapamycin integrates diverse inputs to guide the outcome of antigen recognition in T cells. J. Immunol. 188:10 (2012), 4721–4729.
33. [33] Kim, S.G., Buel, G.R., Blenis, J., Nutrient regulation of the mTOR complex 1 signaling pathway. Mol. Cells 35:6 (2013), 463–473.
34. [34] Pollizzi, K.N., Powell, J.D., Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol. 36:1 (2015), 13–20.
35. [35] Inoki, K., Kim, J., Guan, K.L., AMPK and mTOR in cellular energy homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52 (2012), 381–400.
36. [36] Fernandez-Ramos, A.A., et al. The effect of immunosuppressive molecules on T-cell metabolic reprogramming. Biochimie 127 (2016), 23–36.
37. [37] Brand, K., et al. Cell-cycle-related metabolic and enzymatic events in proliferating rat thymocytes. Eur. J. Biochem. 172:3 (1988), 695–702.
38. [38] Fox, C.J., Hammerman, P.S., Thompson, C.B., Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5:11 (2005), 844–852.
39. [39] Hume, D.A., et al. Aerobic glycolysis and lymphocyte transformation. Biochem. J. 174:3 (1978), 703–709.
40. [40] Loftus, R.M., Finlay, D.K., Immunometabolism: cellular metabolism turns immune regulator. J. Biol. Chem. 291:1 (2016), 1–10.
41. [41] Buck, M.D., O'Sullivan, D., Pearce, E.L., T cell metabolism drives immunity. J. Exp. Med. 212:9 (2015), 1345–1360.
42. [42] Palmer, C.S., et al. Glucose metabolism regulates cell activation differentiation, and functions. Front. Immunol., 6, 2015.
43. [43] Barcia-Vieitez, R., Ramos-Martinez, J.I., The regulation of the oxidative phase of the pentose phosphate pathway: new answers to old problems. IUBMB Life 66:11 (2014), 775–779.
44. [44] Locasale, J.W., Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13:8 (2013), 572–583.
45. [45] Berod, L., et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20:11 (2014), 1327–1333.
46. [46] Cao, Y., Rathmell, J.C., Macintyre, A.N., Metabolic reprogramming towards aerobic glycolysis correlates with greater proliferative ability and resistance to metabolic inhibition in CD8 versus CD4T cells. PLoS One, 9(8), 2014, e104104.
47. [47] Bental, M., Deutsch, C., Metabolic changes in activated T cells: an NMR study of human peripheral blood lymphocytes. Magn. Reson. Med. 29:3 (1993), 317–326.
48. [48] Glick, G.D., et al. Anaplerotic metabolism of alloreactive T cells provides a metabolic approach to treat graft-versus-host disease. J. Pharmacol. Exp. Ther. 351:2 (2014), 298–307.
49. [49] Boukouris, A.E., Zervopoulos, S.D., Michelakis, E.D., Metabolic enzymes moonlighting in the nucleus: metabolic regulation of gene transcription. Trends Biochem. Sci. 41:8 (2016), 712–730.
50. [50] Endo, Y., et al. Obesity drives th17 cell differentiation by inducing the lipid metabolic kinase: ACC1. Cell Rep. 12:6 (2015), 1042–1055.
51. [51] Raha, S., et al. Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease. Eur. J. Immunol. 46:9 (2016), 2233–2238.
52. [52] Lee, J., et al. Regulator of fatty acid metabolism: acetyl coenzyme a carboxylase 1, controls T cell immunity. J. Immunol. 192:7 (2014), 3190–3199.
53. [53] Resh, M.D., Covalent lipid modifications of proteins. Curr. Biol. 23:10 (2013), R431–R435.
54. [54] Rubio, I., et al. TCR-induced activation of Ras proceeds at the plasma membrane and requires palmitoylation of N-Ras. J. Immunol. 185:6 (2010), 3536–3543.
55. [55] Rampoldi, F., et al. Immunosuppression and aberrant t cell development in the absence of N-Myristoylation. J. Immunol. 195:9 (2015), 4228–4243.
56. [56] Marzio, R., Mauel, J., Betz-Corradin, S., CD69 and regulation of the immune function. Immunopharmacol. Immunotoxicol. 21:3 (1999), 565–582.
57. [57] Acuto, O., Michel, F., CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat. Rev. Immunol. 3:12 (2003), 939–951.
58. [58] Filipp, D., et al. Regulation of fyn through translocation of activated lck into lipid rafts. J. Exp. Med. 197:9 (2003), 1221–1227.
59. [59] Nel, A.E., T-cell activation through the antigen receptor. Part 1: Signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. J. Allergy Clin. Immunol. 109:5 (2002), 758–770.
60. [60] Sena, L.A., et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38:2 (2013), 225–236.
61. [61] Chen, Q., et al. Production of reactive oxygen species by mitochondria: central role of complex III. J. Biol. Chem. 278:38 (2003), 36027–36031.
62. [62] Chow, C.W., Rincon, M., Davis, R.J., Requirement for transcription factor NFAT in interleukin-2 expression. Mol. Cell. Biol. 19:3 (1999), 2300–2307.
63. [63] Flescher, E., Bowlin, T.L., Talal, N., Polyamine oxidation down-regulates IL-2 production by human peripheral blood mononuclear cells. J. Immunol. 142:3 (1989), 907–912.
64. [64] Flescher, E., et al. Longitudinal exposure of human T lymphocytes to weak oxidative stress suppresses transmembrane and nuclear signal transduction. J. Immunol. 153:11 (1994), 4880–4889.
65. [65] Freitag, J., et al. Immunometabolism and autoimmunity. Immunol. Cell Biol., 2016 [In press].
66. [66] Quintana, A., et al. T cell activation requires mitochondrial translocation to the immunological synapse. Proc. Natl. Acad. Sci. U. S. A. 104:36 (2007), 14418–14423.
67. [67] Santo-Domingo, J., Demaurex, N., Calcium uptake mechanisms of mitochondria. Biochim. Biophys. Acta 1797:6-7 (2010), 907–912.
68. [68] Ledderose, C., et al. Mitochondria are gate-keepers of T cell function by producing the ATP that drives purinergic signaling. J. Biol. Chem. 289:37 (2014), 25936–25945.
69. [69] Fracchia, K.M., Pai, C.Y., Walsh, C.M., Modulation of t cell metabolism and function through calcium signaling. Front. Immunol., 4(324), 2013.
70. [70] Schwindling, C., et al. Mitochondria positioning controls local calcium influx in T cells. J. Immunol. 184:1 (2010), 184–190.
71. [71] Junger, W.G., Immune cell regulation by autocrine purinergic signalling. Nat. Rev. Immunol. 11:3 (2011), 201–212.
72. [72] Ron-Harel, N., et al. Mitochondrial biogenesis and proteome remodeling promote one-Carbon metabolism for t cell activation. Cell Metab. 24:1 (2016), 104–117.
73. [73] Stover, P.J., One-Carbon Metabolism–Genome interactions in folate-Associated pathologies. J. Nutr. 139:12 (2009), 2402–2405.
74. [74] Ye, J., et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4:12 (2014), 1406–1417.
75. [75] Birsoy, K., et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162:3 (2015), 540–551.
76. [76] Sullivan, L.B., et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162:3 (2015), 552–563.
77. [77] Yusuf, I., Fruman, D.A., Regulation of quiescence in lymphocytes. Trends Immunol. 24:7 (2003), 380–386.
78. [78] Dimeloe, S., et al. The immune-Metabolic basis of effector memory CD4+ t cell function under hypoxic conditions. J. Immunol. 196:1 (2016), 106–114.
79. [79] Buck, M.D., et al. Mitochondrial dynamics controls t cell fate through metabolic programming. Cell 166:1 (2016), 63–76.
80. [80] Song, Z., et al. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing: membrane potential, and Yme1L. J. Cell Biol. 178:5 (2007), 749–755.
81. [81] O'Sullivan, D., et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41:1 (2014), 75–88.
82. [82] van der Windt, G.J., et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc. Natl. Acad. Sci. U. S. A. 110:35 (2013), 14336–14341.
83. [83] Mayer, C.T., Berod, L., Sparwasser, T., Layers of dendritic cell-mediated T cell tolerance, their regulation and the prevention of autoimmunity. Front. Immunol., 3, 2012, 183.
84. [84] Hadis, U., et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34:2 (2011), 237–246.
85. [85] Michalek, R.D., et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186:6 (2011), 3299–3303.
86. [86] Beier, U.H., et al. Essential role of mitochondrial energy metabolism in Foxp3(+) T-regulatory cell function and allograft survival. FASEB J. 29:6 (2015), 2315–2326.
87. [87] Zeng, H., et al. Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cell Mol. Immunol. 12:5 (2015), 566–571.
88. [88] Mascanfroni, I.D., et al. Metabolic control of type 1 regulatory (Tr1) cell differentiation by AHR and HIF1-α. Nat. Med. 21:6 (2015), 638–646.
89. [89] Brown, E.J., et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:6483 (1994), 756–758.
90. [90] Gabardi, S., Baroletti, S.A., Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology. Pharmacotherapy 30:10 (2010), 1044–1056.
91. [91] Baroja-Mazo, A., et al. Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation. World J. Transplant. 6:1 (2016), 183–192.
92. [92] Gharbi, C., Gueutin, V., Izzedine, H., Oedema: solid organ transplantation and mammalian target of rapamycin inhibitor/proliferation signal inhibitors (mTOR-I/PSIs). Clin. Kidney J. 7:2 (2014), 115–120.
93. [93] Laplante, M., Sabatini, D.M., mTOR signaling in growth control and disease. Cell 149:2 (2012), 274–293.
94. [94] Delgoffe, G.M., et al. mTOR differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:6 (2009), 832–844.
95. [95] Battaglia, M., et al. Rapamycin promotes expansion of functional CD4 + CD25 + FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J. Immunol. 177:12 (2006), 8338–8347.
96. [96] Battaglia, M., Stabilini, A., Roncarolo, M.-G., Rapamycin selectively expands CD4 + CD25 + FoxP3+ regulatory T cells. Blood 105:12 (2005), 4743–4748.
97. [97] Delgoffe, G.M., et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12:4 (2011), 295–303.
98. [98] Kurebayashi, Y., et al. PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORgamma. Cell Rep. 1:4 (2012), 360–373.
99. [99] Sasaki, C.Y., et al. p((7)(0)S(6)K(1)) in the TORC1 pathway is essential for the differentiation of Th17Cells: but not Th1, Th2, or Treg cells in mice. Eur. J. Immunol. 46:1 (2016), 212–222.
100. [100] Wu, X., et al. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway. Biochem. Pharmacol. 96:4 (2015), 323–336.
101. [101] Yang, K., et al. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39:6 (2013), 1043–1056.
102. [102] Lee, K., et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32:6 (2010), 743–753.
103. [103] Zeng, H., et al. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499:7459 (2013), 485–490.
104. [104] Procaccini, C., et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33:6 (2010), 929–941.
105. [105] De Rosa, V., et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 26:2 (2007), 241–255.
106. [106] Procaccini, C., et al. The proteomic landscape of human ex vivo regulatory and conventional t cells reveals specific metabolic requirements. Immunity 44:2 (2016), 406–421.
107. [107] Wei, J., et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17:3 (2016), 277–285.
108. [108] Yu, L., et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465:7300 (2010), 942–946.
109. [109] Pollizzi, K.N., et al. Cellular size as a means of tracking mTOR activity and cell fate of CD4+ t cells upon antigen recognition. PLoS One, 10(4), 2015.
110. [110] Pollizzi, K.N., et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat. Immunol. 17:6 (2016), 704–711.
111. [111] Hardie, D.G., et al. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 546:1 (2003), 113–120.
112. [112] Hardie, D.G., Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144:12 (2003), 5179–5183.
113. [113] Gwinn, D.M., et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30:2 (2008), 214–226.
114. [114] Xu, J., Ji, J., Yan, X.H., Cross-talk between AMPK and mTOR in regulating energy balance. Crit. Rev. Food Sci. Nutr. 52:5 (2012), 373–381.
115. [115] Zhao, D., et al. Metformin decreases IL-22 secretion to suppress tumor growth in an orthotopic mouse model of hepatocellular carcinoma. Int. J. Cancer 136:11 (2015), 2556–2565.
116. [116] Kang, K.Y., et al. Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int. Immunopharmacol. 16:1 (2013), 85–92.
117. [117] Bai, A., et al. Novel anti-inflammatory action of 5-aminoimidazole-4-carboxamide ribonucleoside with protective effect in dextran sulfate sodium-induced acute and chronic colitis. J. Pharmacol. Exp. Ther. 333:3 (2010), 717–725.
118. [118] Son, H.J., Lee, J., Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediat. Inflamm., 2014, 2014 (p. 973986).
119. [119] Lee, S.Y., et al. Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance. PLoS One, 10(9), 2015, e0135858.
120. [120] Bai, A., et al. AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochem. Pharmacol. 80:11 (2010), 1708–1717.
121. [121] Nath, N., et al. 5-aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis. J. Immunol. 175:1 (2005), 566–574.
122. [122] Gualdoni, G.A., et al. The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation. FASEB J., 2016.
123. [123] Andrzejewski, S., et al. Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab., 2, 2014, 12.
124. [124] Wheaton, W.W., et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife, 3, 2014, p. e02242.
125. [125] Tamas, P., et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med. 203:7 (2006), 1665–1670.
126. [126] Andris, F., Leo, O., AMPK in lymphocyte metabolism and function. Int. Rev. Immunol. 34:1 (2015), 67–81.
127. [127] Woods, A., et al. Ca2+/calmodulin-dependent protein kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2:1 (2005), 21–33.
128. [128] Mayer, A., et al. AMP-activated protein kinase regulates lymphocyte responses to metabolic stress but is largely dispensable for immune cell development and function. Eur. J. Immunol. 38:4 (2008), 948–956.
129. [129] Blagih, J., et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 42:1 (2015), 41–54.
130. [130] Kim, Y., et al. Hypoxic tumor microenvironment and cancer cell differentiation. Curr. Mol. Med. 9:4 (2009), 425–434.
131. [131] Navratilova, J., et al. Low-glucose conditions of tumor microenvironment enhance cytotoxicity of tetrathiomolybdate to neuroblastoma cells. Nutr. Cancer 65:5 (2013), 702–710.
132. [132] Chang, C.H., et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:6 (2015), 1229–1241.
133. [133] Wang, C., et al. CD5L/AIM regulates lipid biosynthesis and restrains th17 cell pathogenicity. Cell 163:6 (2015), 1413–1427.
134. [134] Hu, X., et al. Sterol metabolism controls T(H)17 differentiation by generating endogenous RORgamma agonists. Nat. Chem. Biol. 11:2 (2015), 141–147.
135. [135] Panda, T., et al. Kinetic mechanisms of cholesterol synthesis: a review. Ind. Eng. Chem. Res. 50:23 (2011), 12847–12864.
136. [136] Gerriets, V.A., et al. Metabolic programming and PDHK1 control CD4 + T cell subsets and inflammation. J. Clin. Invest. 125:1 (2015), 194–207.
137. [137] Huang, S.C.C., et al. Cell-intrinsic lysosomal lipolysis is essential for macrophage alternative activation. Nat. Immunol. 15:9 (2014), 846–855.
138. [138] Nomura, M., et al. Fatty acid oxidation in macrophage polarization. Nat. Immunol. 17:3 (2016), 216–217.
139. [139] Byersdorfer, C.A., et al. T Effector cells require fatty acid metabolism during murine graft-versus-host disease. Blood 122:18 (2013), 3230–3237.
140. [140] Link, H., et al. Real-time metabolome profiling of the metabolic switch between starvation and growth. Nat. Methods 12:11 (2015), 1091–1097.
141. [141] O'Neill, L.A.J., Kishton, R.J., Rathmell, J., A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16:9 (2016), 553–565.