1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Immunology
  4. Volume 36, 2018
  5. Article

Annual Review of Immunology

Volume 36, 2018

Unraveling the Complex Interplay Between T Cell Metabolism and Function

Abstract

Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies.

Keyword(s): immunometabolism, immunotherapy, plasticity, T cell function
Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-042617-053019
2018-04-26
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/immunol/36/1/annurev-immunol-042617-053019.html?itemId=/content/journals/10.1146/annurev-immunol-042617-053019&mimeType=html&fmt=ahah

Literature Cited

  1. Weiner HL, Frenkel D. 1.  2006. Immunology and immunotherapy of Alzheimer's disease. Nat. Rev. Immunol. 6404–16
  2. Heppner FL, Ransohoff RM, Becher B. 2.  2015. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16358–72
  3. Saltiel AR, Olefsky JM. 3.  2017. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Investig. 1271–4
  4. Mathis D. 4.  2013. Immunological goings-on in visceral adipose tissue. Cell Metab 17851–59
  5. Warburg O. 5.  1925. The metabolism of carcinoma cells. J. Cancer Res. 9148–63
  6. Vander Heiden MG, Cantley LC, Thompson CB. 6.  2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 3241029–33
  7. Mills EL, Kelly B, O'Neill LAJ. 7.  2017. Mitochondria are the powerhouses of immunity. Nat. Immunol. 18488–98
  8. Houten SM, Violante S, Ventura FV, Wanders RJA. 8.  2016. The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Annu. Rev. Physiol. 7823–44
  9. Schieber M, Chandel NS. 9.  2014. ROS function in redox signaling and oxidative stress. Curr. Biol. 24R453–62
  10. MacIver NJ, Michalek RD, Rathmell JC. 10.  2013. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31259–83
  11. Brownlie RJ, Zamoyska R. 11.  2013. T cell receptor signalling networks: branched, diversified and bounded. Nat. Rev. Immunol. 13257–69
  12. Saxton RA, Sabatini DM. 12.  2017. mTOR signaling in growth, metabolism, and disease. Cell 168960–76
  13. Yang K, Neale G, Green DR, He W, Chi H. 13.  2011. The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat. Immunol. 12888–97
  14. Cekic C, Sag D, Day YJ, Linden J. 14.  2013. Extracellular adenosine regulates naive T cell development and peripheral maintenance. J. Exp. Med. 2102693–706
  15. Cunningham CA, Bergsbaken T, Fink PJ. 15.  2017. Cutting edge: Defective aerobic glycolysis defines the distinct effector function in antigen-activated CD8+ recent thymic emigrants. J. Immunol. 1984575–80
  16. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R. 16.  et al. 2011. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35871–82
  17. Pollizzi KN, Patel CH, Sun IH, Oh MH, Waickman AT. 17.  et al. 2015. mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation. J. Clin. Investig. 1252090–108
  18. Boyman O, Sprent J. 18.  2012. The role of interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol. 12180–90
  19. Mendoza A, Fang V, Chen C, Serasinghe M, Verma A. 19.  et al. 2017. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature 546158–61
  20. Malissen B, Bongrand P. 20.  2015. Early T cell activation: integrating biochemical, structural, and biophysical cues. Annu. Rev. Immunol. 33539–61
  21. Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA. 21.  2016. CD28 costimulation: from mechanism to therapy. Immunity 44973–88
  22. Patel CH, Powell JD. 22.  2017. Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease. Curr. Opin. Immunol. 4682–88
  23. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. 23.  2012. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 3039–68
  24. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA. 24.  et al. 2013. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38225–36
  25. Previte DM, O'Connor EC, Novak EA, Martins CP, Mollen KP, Piganelli JD. 25.  2017. Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation. PLOS ONE 12e0175549
  26. Jackson SH, Devadas S, Kwon J, Pinto LA, Williams MS. 26.  2004. T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat. Immunol. 5818–27
  27. Mak TW, Grusdat M, Duncan GS, Dostert C, Nonnenmacher Y. 27.  et al. 2017. Glutathione primes T cell metabolism for inflammation. Immunity 461089–90
  28. Siska PJ, Kim B, Ji X, Hoeksema MD, Massion PP. 28.  et al. 2016. Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes. J. Immunol. Methods 43851–58
  29. Laniewski NG, Grayson JM. 29.  2004. Antioxidant treatment reduces expansion and contraction of antigen-specific CD8+ T cells during primary but not secondary viral infection. J. Virol. 7811246–57
  30. Chandel NS. 30.  2015. Evolution of mitochondria as signaling organelles. Cell Metab 22204–6
  31. Jones RG, Pearce EJ. 31.  2017. MenTORing immunity: mTOR signaling in the development and function of tissue-resident immune cells. Immunity 46730–42
  32. Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM. 32.  et al. 2007. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 3151687–91
  33. Verbist KC, Guy CS, Milasta S, Liedmann S, Kaminski MM. 33.  et al. 2016. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532389–93
  34. Pollizzi KN, Sun IH, Patel CH, Lo YC, Oh MH. 34.  et al. 2016. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8+ T cell differentiation. Nat. Immunol. 17704–11
  35. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. 35.  2013. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14500–8
  36. Chang C-H, Curtis JD, Maggi LB Jr., Faubert B, Villarino AV. 36.  et al. 2013. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 1531239–51
  37. Tan H, Yang K, Li Y, Shaw TI, Wang Y. 37.  et al. 2017. Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation. Immunity 46488–503
  38. Tarasenko TN, Pacheco SE, Koenig MK, Gomez-Rodriguez J, Kapnick SM. 38.  et al. 2017. Cytochrome c oxidase activity is a metabolic checkpoint that regulates cell fate decisions during T cell activation and differentiation. Cell Metab 251254–68.e7
  39. Hukelmann JL, Anderson KE, Sinclair LV, Grzes KM, Murillo AB. 39.  et al. 2016. The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat. Immunol. 17104–12
  40. Gomes LC, Di Benedetto G, Scorrano L. 40.  2011. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13589–98
  41. Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L. 41.  et al. 2006. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126163–75
  42. Hentze MW, Preiss T. 42.  2010. The REM phase of gene regulation. Trends Biochem. Sci. 35423–26
  43. Peng C, Lu Z, Xie Z, Cheng Z, Chen Y. 43.  et al. 2011. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell Proteom. 10M111.012658
  44. Zhang Z, Tan M, Xie Z, Dai L, Chen Y, Zhao Y. 44.  2011. Identification of lysine succinylation as a new post-translational modification. Nat. Chem. Biol. 758–63
  45. Nishida Y, Rardin MJ, Carrico C, He W, Sahu AK. 45.  et al. 2015. SIRT5 regulates both cytosolic and mitochondrial protein malonylation with glycolysis as a major target. Mol. Cell 59321–32
  46. Moellering RE, Cravatt BF. 46.  2013. Functional lysine modification by an intrinsically reactive primary glycolytic metabolite. Science 341549–53
  47. Swamy M, Pathak S, Grzes KM, Damerow S, Sinclair LV. 47.  et al. 2016. Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat. Immunol. 17712–20
  48. Araujo L, Khim P, Mkhikian H, Mortales C-L, Demetriou M. 48.  2017. Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. eLife 6e21330
  49. Chien M-W, Lin M-H, Huang S-H, Fu S-H, Hsu C-Y. 49.  et al. 2015. Glucosamine modulates T cell differentiation through down-regulating N-linked glycosylation of CD25. J. Biol. Chem. 29029329–44
  50. Asano T, Takata K, Katagiri H, Ishihara H, Inukai K. 50.  et al. 1993. The role of N-glycosylation in the targeting and stability of GLUT1 glucose transporter. FEBS Lett 324258–61
  51. Console L, Scalise M, Tarmakova Z, Coe IR, Indiveri C. 51.  2015. N-linked glycosylation of human SLC1A5 (ASCT2) transporter is critical for trafficking to membrane. Biochim. Biophys. Acta 18531636–45
  52. Puleston DJ, Villa M, Pearce EL. 52.  2017. Ancillary activity: beyond core metabolism in immune cells. Cell Metab 26131–41
  53. Mowen KA, David M. 53.  2014. Unconventional post-translational modifications in immunological signaling. Nat. Immunol. 15512–20
  54. Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A. 54.  et al. 2016. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab 24104–17
  55. Ma EH, Bantug G, Griss T, Condotta S, Johnson RM. 55.  et al. 2017. Serine is an essential metabolite for effector T cell expansion. Cell Metab 25345–57 Correction. 2017 Cell Metab 25482
  56. MacIver NJ, Blagih J, Saucillo DC, Tonelli L, Griss T. 56.  et al. 2011. The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J. Immunol. 1874187–98
  57. Mayer A, Denanglaire S, Viollet B, Leo O, Andris F. 57.  2008. AMP-activated protein kinase regulates lymphocyte responses to metabolic stress but is largely dispensable for immune cell development and function. Eur. J. Immunol. 38948–56
  58. Tamás P, Hawley SA, Clarke RG, Mustard KJ, Green K. 58.  et al. 2006. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med 2031665–70
  59. Adams WC, Chen Y-H, Kratchmarov R, Yen B, Nish SA. 59.  et al. 2016. Anabolism-associated mitochondrial stasis driving lymphocyte differentiation over self-renewal. Cell Rep 173142–52
  60. Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vazquez G. 60.  et al. 2015. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 4241–54
  61. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA. 61.  et al. 2011. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331456–61
  62. Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE. 62.  et al. 2016. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45374–88 Correction. 2016 Immunity 45701–3
  63. Rabinovitch RC, Samborska B, Faubert B, Ma EH, Gravel SP. 63.  et al. 2017. AMPK maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species. Cell Rep 211–9
  64. Lee J, Walsh MC, Hoehn KL, James DE, Wherry EJ, Choi Y. 64.  2014. Regulator of fatty acid metabolism, acetyl coenzyme A carboxylase 1, controls T cell immunity. J. Immunol. 1923190–99
  65. Lee JE, Walsh MC, Hoehn KL, James DE, Wherry EJ, Choi Y. 65.  2015. Acetyl CoA carboxylase 2 is dispensable for CD8+ T cell responses. PLOS ONE 10e0137776
  66. Saha AK, Ruderman NB. 66.  2003. Malonyl-CoA and AMP-activated protein kinase: an expanding partnership. Mol. Cell Biochem. 25365–70
  67. Hosios AM, Hecht VC, Danai LV, Johnson MO, Rathmell JC. 67.  et al. 2016. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev. Cell 36540–49
  68. Liberti MV, Locasale JW. 68.  2016. The Warburg Effect: How does it benefit cancer cells?. Trends Biochem. Sci. 41211–18
  69. Fox CJ, Hammerman PS, Thompson CB. 69.  2005. Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5844–52
  70. Franchi L, Monteleone I, Hao L-Y, Spahr MA, Zhao W. 70.  et al. 2017. Inhibiting oxidative phosphorylation in vivo restrains Th17 effector responses and ameliorates murine colitis. J. Immunol. 1982735–46
  71. Buck MD, O'Sullivan D, Klein Geltink RI, Curtis JD, Chang C-H. 71.  et al. 2016. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 16663–76
  72. O'Sullivan D, van der Windt GJW, Huang SC-C, Curtis JD, Chang C-H. 72.  et al. 2014. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 4175–88
  73. Buck MD, Sowell RT, Kaech SM, Pearce EL. 73.  2017. Metabolic instruction of immunity. Cell 169570–86
  74. Jacobs SR, Herman CE, MacIver NJ, Wofford JA, Wieman HL. 74.  et al. 2008. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J. Immunol. 1804476–86
  75. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC. 75.  et al. 2014. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 2061–72
  76. Shi L, Tu BP. 76.  2015. Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr. Opin. Cell Biol. 33125–31
  77. Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. 77.  2016. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354481–84
  78. Chang C-H, Qiu J, O'Sullivan D, Buck MD, Noguchi T. 78.  et al. 2015. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 1621229–41
  79. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X. 79.  et al. 2015. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 1621217–28
  80. Zhao E, Maj T, Kryczek I, Li W, Wu K. 80.  et al. 2016. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nature Immunol 1795–103
  81. Siska PJ, van der Windt GJW, Kishton RJ, Cohen S, Eisner W. 81.  et al. 2016. Suppression of Glut1 and glucose metabolism by decreased Akt/mTORC1 signaling drives T cell impairment in B cell leukemia. J. Immunol. 1972532–40
  82. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B. 82.  et al. 2015. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 66692
  83. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. 83.  2016. Coinhibitory pathways in immunotherapy for cancer. Annu. Rev. Immunol. 34539–73
  84. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV. 84.  et al. 2013. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. . Immunol 141173–82
  85. Phan AT, Doedens AL, Palazon A, Tyrakis PA, Cheung KP. 85.  et al. 2016. Constitutive glycolytic metabolism supports CD8+ T cell effector memory differentiation during viral infection. Immunity 451024–37
  86. van der Windt GJ, O'Sullivan D, Everts B, Huang SC, Buck MD. 86.  et al. 2013. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. PNAS 11014336–41
  87. Gubser PM, Bantug GR, Razik L, Fischer M, Dimeloe S. 87.  et al. 2013. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 141064–72
  88. Balmer ML, Hess C. 88.  2016. Feeling worn out? PGC1α to the rescue for dysfunctional mitochondria in T cell exhaustion. Immunity 45233–35
  89. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC. 89.  et al. 2002. The CD28 signaling pathway regulates glucose metabolism. Immunity 16769–77
  90. Choi BK, Lee DY, Lee DG, Kim YH, Kim S-H. 90.  et al. 2017. 4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation. Cell Mol. Immunol. 14748–57
  91. Cannons JL, Lau P, Ghumman B, DeBenedette MA, Yagita H. 91.  et al. 2001. 4–1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. J. Immunol. 1671313–24
  92. Balmer ML, Ma EH, Bantug GR, Grählert J, Pfister S. 92.  et al. 2016. Memory CD8+ T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 441312–24
  93. Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE. 93.  et al. 2016. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45358–73
  94. Zhang CS, Hawley SA, Zong Y, Li M, Wang Z. 94.  et al. 2017. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548112–16
  95. Hu H, Juvekar A, Lyssiotis CA, Lien EC, Albeck JG. 95.  et al. 2016. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell 164433–46
  96. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ. 96.  et al. 2011. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12295–303
  97. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL. 97.  et al. 2009. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30832–44
  98. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ. 98.  et al. 2011. Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 1863299–303
  99. Battaglia M, Stabilini A, Roncarolo M-G. 99.  2005. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 1054743–48
  100. Valmori D, Tosello V, Souleimanian NE, Godefroy E, Scotto L. 100.  et al. 2006. Rapamycin-mediated enrichment of T cells with regulatory activity in stimulated CD4+ T cell cultures is not due to the selective expansion of naturally occurring regulatory T cells but to the induction of regulatory functions in conventional CD4+ T cells. J. Immunol. 177944–49
  101. Kang J, Huddleston SJ, Fraser JM, Khoruts A. 101.  2008. De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR. J. Leukoc. Biol. 831230–39
  102. Yang K, Shrestha S, Zeng H, Karmaus PW, Neale G. 102.  et al. 2013. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 391043–56
  103. Heikamp EB, Patel CH, Collins S, Waickman A. 103. , Oh M-H, et al. 2014. The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat. Immunol. 15457–64
  104. Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA. 104.  et al. 2004. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 61122–28
  105. Yang J-Q, Kalim KW, Li Y, Zhang S, Hinge A. 105.  et al. 2016. RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation. J. Allergy Clin. Immunol. 137231–45.e4
  106. Zhao FQ, Keating AF. 106.  2007. Functional properties and genomics of glucose transporters. Curr. Genom. 8113–28
  107. Chornoguz O, Hagan RS, Haile A, Arwood ML, Gamper CJ. 107.  et al. 2017. mTORC1 promotes T-bet phosphorylation to regulate Th1 differentiation. J. Immunol. 1983939–48
  108. Kurobe H, Urata M, Ueno M, Ueki M, Ono S. 108.  et al. 2010. Role of hypoxia-inducible factor 1α in T cells as a negative regulator in development of vascular remodeling. Arterioscler. Thromb. Vasc. Biol. 30210–17
  109. Shehade H, Acolty V, Moser M, Oldenhove G. 109.  2015. Cutting edge: Hypoxia-inducible factor 1 negatively regulates Th1 function. J. Immunol. 1951372–76
  110. Metzler B, Gfeller P, Guinet E. 110.  2016. Restricting glutamine or glutamine-dependent purine and pyrimidine syntheses promotes human T cells with high FOXP3 expression and regulatory properties. J. Immunol. 1963618–30
  111. Klysz D, Tai X, Robert PA, Craveiro M, Cretenet G. 111.  et al. 2015. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8ra97
  112. Xu T, Stewart KM, Wang X, Liu K, Xie M. 112.  et al. 2017. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature 548228–33
  113. Abdel Rahman AM, Ryczko M, Pawling J, Dennis JW. 113.  2013. Probing the hexosamine biosynthetic pathway in human tumor cells by multitargeted tandem mass spectrometry. ACS Chem. Biol. 82053–62
  114. Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E. 114.  et al. 2010. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 1851037–44
  115. Crotty S. 115.  2014. T follicular helper cell differentiation, function, and roles in disease. Immunity 41529–42
  116. Oestreich KJ, Read KA, Gilbertson SE, Hough KP, McDonald PW. 116.  et al. 2014. Bcl-6 directly represses the gene program of the glycolysis pathway. Nat. Immunol. 15957–64
  117. Ray JP, Staron MM, Shyer JA, Ho P-C, Marshall HD. 117.  et al. 2015. The interleukin-2-mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43690–702
  118. Zeng H, Cohen S, Guy C, Shrestha S, Neale G. 118.  et al. 2016. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 45540–54
  119. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S. 119.  et al. 2014. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med.20:1327–33 Erratum. 2015 Nat. Med. 21414 [Google Scholar]
  120. Gaffen SL, Jain R, Garg AV, Cua DJ. 120.  2014. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14585–600
  121. Endo Y, Asou HK, Matsugae N, Hirahara K, Shinoda K. 121.  et al. 2015. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep 121042–55
  122. Raha S, Raud B, Oberdörfer L, Castro CN, Schreder A. 122.  et al. 2016. Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease. Eur. J. Immunol. 462233–38
  123. Ye J, DeBose-Boyd RA. 123.  2011. Regulation of cholesterol and fatty acid synthesis. Cold Spring Harb. Perspect. Biol. 3a004754
  124. Angela M, Endo Y, Asou HK, Yamamoto T, Tumes DJ. 124.  et al. 2016. Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells. Nat. Commun. 713683
  125. Muroski ME, Miska J, Chang AL, Zhang P, Rashidi A. 125.  et al. 2017. Fatty acid uptake in T cell subsets using a quantum dot fatty acid conjugate. Sci. Rep. 75790
  126. Hu X, Wang Y, Hao L-Y, Liu X, Lesch CA. 126.  et al. 2015. Sterol metabolism controls TH17 differentiation by generating endogenous RORγ agonists. Nat. Chem. Biol. 11141–47 Corrigendum. 2015 Nat. Chem. Biol. 11741 [Google Scholar]
  127. Santori FR, Huang P, van de Pavert SA, Douglass EF, Leaver DJ. 127.  et al. 2015. Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab 21286–97
  128. Wang C, Yosef N, Gaublomme J, Wu C, Lee Y. 128.  et al. 2015. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 1631413–27
  129. Makki K, Froguel P, Wolowczuk I. 129.  2013. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm 2013139239
  130. Saucillo DC, Gerriets VA, Sheng J, Rathmell JC, MacIver NJ. 130.  2014. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J. Immunol. 192136–44
  131. Papathanassoglou E, El-Haschimi K, Li XC, Matarese G, Strom T, Mantzoros C. 131.  2006. Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. J. Immunol. 1767745–52
  132. Reis BS, Lee K, Fanok MH, Mascaraque C, Amoury M. 132.  et al. 2015. Leptin receptor signaling in T cells is required for Th17 differentiation. J. Immunol. 1945253–60
  133. Gerriets VA, Danzaki K, Kishton RJ, Eisner W, Nichols AG. 133.  et al. 2016. Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity. Eur. J. Immunol. 461970–83
  134. De Rosa V, Procaccini C, Calì G, Pirozzi G, Fontana S. 134.  et al. 2007. A key role of leptin in the control of regulatory T cell proliferation. Immunity 26241–55
  135. Newton R, Priyadharshini B, Turka LA. 135.  2016. Immunometabolism of regulatory T cells. Nat. Immunol. 17618–25
  136. Travis MA, Sheppard D. 136.  2014. TGF-β activation and function in immunity. Annu. Rev. Immunol. 3251–82
  137. Xie M, Zhang D, Dyck JR, Li Y, Zhang H. 137.  et al. 2006. A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. PNAS 10317378–83
  138. Gualdoni GA, Mayer KA, Goschl L, Boucheron N, Ellmeier W, Zlabinger GJ. 138.  2016. The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation. FASEB J 303800–9
  139. He N, Fan W, Henriquez B, Yu RT, Atkins AR. 139.  et al. 2017. Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. PNAS 11412542–47
  140. Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J. 140.  et al. 2015. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. 16188–96
  141. Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H. 141.  2015. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat. Immunol. 16178–87
  142. Sharma MD, Shinde R, McGaha TL, Huang L, Holmgaard RB. 142.  et al. 2015. The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci. Adv. 1e1500845
  143. Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H. 143.  2013. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499485–90
  144. Forero-Peña DA, Gutierrez FRS. 144.  2013. Statins as modulators of regulatory T-cell biology. Mediators Inflamm 2013167086
  145. De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M. 145.  et al. 2015. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat. Immunol. 161174–84
  146. Wei J, Long L, Yang K, Guy C, Shrestha S. 146.  et al. 2016. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17277–85
  147. Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L. 147.  et al. 2017. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 251282–93.e7
  148. Procaccini C, Carbone F, Di Silvestre D, Brambilla F, De Rosa V. 148.  et al. 2016. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity 44406–21 Correction. 2016 Immunity 44712
  149. Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ. 149.  et al. 2016. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nature Immunol 171459–66
  150. Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G. 150.  et al. 2017. Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity 47875–89.e10
  151. Kolodin D, van Panhuys N, Li C, Magnuson AM, Cipolletta D. 151.  et al. 2015. Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab 21543–57
  152. Cipolletta D, Feuerer M, Li A, Kamei N, Lee J. 152.  et al. 2012. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486549–53
  153. Munn DH, Bronte V. 153.  2016. Immune suppressive mechanisms in the tumor microenvironment. Curr. Opin. Immunol. 391–6
  154. Maj T, Wang W, Crespo J, Zhang H, Wang W. 154.  et al. 2017. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 181332–41
  155. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H. 155.  et al. 2009. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460103–7
  156. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA. 156.  et al. 2009. mTOR regulates memory CD8 T-cell differentiation. Nature 460108–12
  157. Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG. 157.  et al. 2013. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Investig. 1234479–88
  158. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM. 158.  et al. 2011. A human memory T cell subset with stem cell-like properties. Nat. Med. 171290–97
  159. Sukumar M, Liu J, Mehta GU, Patel SJ, Roychoudhuri R. 159.  et al. 2016. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab 2363–76
  160. Crompton JG, Sukumar M, Roychoudhuri R, Clever D, Gros A. 160.  et al. 2015. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res 75296–305
  161. van der Windt GJW, Everts B, Chang C-H, Curtis JD, Freitas TC. 161.  et al. 2012. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 3668–78
  162. Pfleger J, He M, Abdellatif M. 162.  2015. Mitochondrial complex II is a source of the reserve respiratory capacity that is regulated by metabolic sensors and promotes cell survival. Cell Death Dis 6e1835
  163. Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA. 163.  2013. AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur. J. Immunol. 43889–96
  164. Dimeloe S, Mehling M, Frick C, Loeliger J, Bantug GR. 164.  et al. 2016. The immune-metabolic basis of effector memory CD4+ T cell function under hypoxic conditions. J. Immunol. 196106–14
  165. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R. 165.  et al. 2013. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155160–71
  166. Klein Geltink RI, O'Sullivan D, Corrado M, Bremser A, Buck MD. 166.  et al. 2017. Mitochondrial priming by CD28. Cell 171385–97.e11
  167. Champagne DP, Hatle KM, Fortner KA, D'Alessandro A, Thornton TM. 167.  et al. 2016. Fine-tuning of CD8+ T cell mitochondrial metabolism by the respiratory chain repressor MCJ dictates protection to influenza virus. Immunity 441299–311
  168. Lochner M, Berod L, Sparwasser T. 168.  2015. Fatty acid metabolism in the regulation of T cell function. Trends Immunol 3681–91
  169. Cui G, Staron MM, Gray SM, Ho PC, Amezquita RA. 169.  et al. 2015. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T cell longevity. Cell 161750–61
  170. Pan Y, Tian T, Park CO, Lofftus SY, Mei S. 170.  et al. 2017. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543252–56
  171. O'Sullivan D, Pearce EL. 171.  2015. Targeting T cell metabolism for therapy. Trends Immunol 3671–80
  172. Minn AJ, Wherry EJ. 172.  2016. Combination cancer therapies with immune checkpoint blockade: convergence on interferon signaling. Cell 165272–75
  173. Swart M, Verbrugge I, Beltman JB. 173.  2016. Combination approaches with immune-checkpoint blockade in cancer therapy. Front. Oncol. 6233
  174. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. 174.  2017. Cancer immunotherapy—immune checkpoint blockade and associated endocrinopathies. Nat. Rev. Endocrinol. 13195–207
  175. Lim WA, June CH. 175.  2017. The principles of engineering immune cells to treat cancer. Cell 168724–40
  176. Yu S, Li A, Liu Q, Li T, Yuan X. 176.  et al. 2017. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J. Hematol. Oncol. 1078
  177. Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE. 177.  et al. 2016. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44380–90
  178. Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS. 178.  et al. 2016. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Investig. 1263130–44
  179. Crompton JG, Sukumar M, Restifo NP. 179.  2016. Targeting Akt in cell transfer immunotherapy for cancer. Oncoimmunology 5e1014776
  180. Zheng Y, Delgoffe GM, Meyer CF, Chan W, Powell JD. 180.  2009. Anergic T cells are metabolically anergic. J. Immunol. 1836095–101
  181. Nguyen DX, Bos PD, Massague J. 181.  2009. Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 9274–84
  182. Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M. 182.  et al. 2016. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 1661117–31.e14
/content/journals/10.1146/annurev-immunol-042617-053019
Loading
Unraveling the Complex Interplay Between T Cell Metabolism and Function
Annual Review of Immunology 36, 461 (2018); https://doi.org/10.1146/annurev-immunol-042617-053019
/content/journals/10.1146/annurev-immunol-042617-053019
/content/journals/10.1146/annurev-immunol-042617-053019
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error