Skip to main content
SpringerLink
Log in
Book cover

Immune Metabolism in Health and Tumor pp 131–152Cite as

Transcriptional Regulation of T Cell Metabolism Reprograming

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1011))

Abstract

T cell activation, differentiation, and function are tightly regulated by a complex network of transcription factors, epigenetic modifications, and signaling pathways of both TCR and cytokines. Over the past decade, it is increasingly clear that T cell immune responses are also regulated by their associated metabolic reprograming. Compared with relatively well-understood transcriptional regulation of T cell activation, differentiation, and function, less is known about the transcriptional regulation of T cell metabolic reprograming during T cell immune responses. In this review, we first describe how signaling pathways of TCR and cytokines regulate metabolic reprograming and then focus on transcription factors that control metabolic pathways and outcomes of T cell immune responses. A better understanding of T cell metabolic regulation will provide new strategies and targets for the treatment of T cell-related diseases.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28:445–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ahmed R, Gray D (1996) Immunological memory and protective immunity: understanding their relation. Science 272(5258):54–60

    Article  CAS  PubMed  Google Scholar 

  3. Harrington LE, Janowski KM, Oliver JR, Zajac AJ, Weaver CT (2008) Memory CD4 T cells emerge from effector T-cell progenitors. Nature 452(7185):356–360

    Article  CAS  PubMed  Google Scholar 

  4. Zhu J, Paul WE (2010) Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 238(1):247–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Williams MA, Bevan MJ (2007) Effector and memory CTL differentiation. Annu Rev Immunol 25:171–192

    Article  CAS  PubMed  Google Scholar 

  6. Joshi NS, Kaech SM (2008) Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. J Immunol 180(3):1309–1315

    Article  CAS  PubMed  Google Scholar 

  7. Kaech SM, Cui W (2012) Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 12(11):749–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jameson SC, Masopust D (2009) Diversity in T cell memory: an embarrassment of riches. Immunity 31(6):859–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kaech SM, Wherry EJ (2007) Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 27(3):393–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Man K, Kallies A (2015) Synchronizing transcriptional control of T cell metabolism and function. Nat Rev Immunol 15(9):574–584

    Article  CAS  PubMed  Google Scholar 

  11. Hough KP, Chisolm DA, Weinmann AS (2015) Transcriptional regulation of T cell metabolism. Mol Immunol 68(2 Pt C):520–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pearce EL (2010) Metabolism in T cell activation and differentiation. Curr Opin Immunol 22(3):314–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38(4):633–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pearce EL, Poffenberger MC, Chang CH, Jones RG (2013) Fueling immunity: insights into metabolism and lymphocyte function. Science 342(6155):1242454

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Lochner M, Berod L, Sparwasser T (2015) Fatty acid metabolism in the regulation of T cell function. Trends Immunol 36(2):81–91

    Article  CAS  PubMed  Google Scholar 

  16. Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    Article  CAS  PubMed  Google Scholar 

  17. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lunt SY, Vander Heiden MG (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 27:441–464

    Article  CAS  PubMed  Google Scholar 

  19. MacIver NJ, Michalek RD, Rathmell JC (2013) Metabolic regulation of T lymphocytes. Annu Rev Immunol 31:259–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rudolph MG, Stanfield RL, Wilson IA (2006) How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol 24:419–466

    Article  CAS  PubMed  Google Scholar 

  21. Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rossjohn J, Gras S, Miles JJ, Turner SJ, Godfrey DI, McCluskey J (2015) T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol 33:169–200

    Article  CAS  PubMed  Google Scholar 

  23. Navarro MN, Cantrell DA (2014) Serine-threonine kinases in TCR signaling. Nat Immunol 15(9):808–814

    Article  CAS  PubMed  Google Scholar 

  24. Malissen B, Bongrand P (2015) Early T cell activation: integrating biochemical, structural, and biophysical cues. Annu Rev Immunol 33:539–561

    Article  CAS  PubMed  Google Scholar 

  25. Guy CS, Vignali KM, Temirov J, Bettini ML, Overacre AE, Smeltzer M et al (2013) Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nat Immunol 14(3):262–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D et al (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35(6):871–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR et al (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208(7):1367–1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Man K, Miasari M, Shi W, Xin A, Henstridge DC, Preston S et al (2013) The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat Immunol 14(11):1155–1165

    Article  CAS  PubMed  Google Scholar 

  29. Kidani Y, Elsaesser H, Hock MB, Vergnes L, Williams KJ, Argus JP et al (2013) Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol 14(5):489–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chou C, Pinto AK, Curtis JD, Persaud SP, Cella M, Lin CC et al (2014) c-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells. Nat Immunol 15(9):884–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Buchholz VR, Schumacher TN, Busch DH (2015) T cell fate at the single-cell level. Annu Rev Immunol 34:65

    Article  PubMed  CAS  Google Scholar 

  32. Chi H (2012) Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12(5):325–338

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Waickman AT, Powell JD (2012) mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev 249(1):43–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pollizzi KN, Powell JD (2014) Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat Rev Immunol 14(7):435–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY et al (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127(1):125–137

    Article  CAS  PubMed  Google Scholar 

  37. Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL (2008) Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J 27(14):1919–1931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yan L, Mieulet V, Lamb RF (2008) mTORC2 is the hydrophobic motif kinase for SGK1. Biochem J 416(3):e19–e21

    Article  CAS  PubMed  Google Scholar 

  39. Garcia-Martinez JM, Alessi DR (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 416(3):375–385

    Article  CAS  PubMed  Google Scholar 

  40. Macintyre AN, Finlay D, Preston G, Sinclair LV, Waugh CM, Tamas P et al (2011) Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. Immunity 34(2):224–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL, Rolf J et al (2012) PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med 209(13):2441–2453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Turner MS, Kane LP, Morel PA (2009) Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion. J Immunol 183(8):4895–4903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Katzman SD, O’Gorman WE, Villarino AV, Gallo E, Friedman RS, Krummel MF et al (2010) Duration of antigen receptor signaling determines T-cell tolerance or activation. Proc Natl Acad Sci U S A 107(42):18085–18090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B et al (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30(6):832–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E et al (2013) Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 14(11):1173–1182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR 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 12(4):295–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S, Killeen N et al (2010) Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32(6):743–753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang CY et al (2011) Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U S A 108(45):18348–18353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Colombetti S, Basso V, Mueller DL, Mondino A (2006) Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin. J Immunol 176(5):2730–2738

    Article  CAS  PubMed  Google Scholar 

  50. Zheng Y, Collins SL, Lutz MA, Allen AN, Kole TP, Zarek PE et al (2007) A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol 178(4):2163–2170

    Article  CAS  PubMed  Google Scholar 

  51. Zheng Y, Delgoffe GM, Meyer CF, Chan W, Powell JD (2009) Anergic T cells are metabolically anergic. J Immunol 183(10):6095–6101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. So T, Choi H, Croft M (2011) OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling. J Immunol 186(6):3547–3555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK et al (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206(13):3015–3029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rochman Y, Spolski R, Leonard WJ (2009) New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 9(7):480–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS et al (1993) Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73(1):147–157

    Article  CAS  PubMed  Google Scholar 

  56. Liao W, Lin JX, Leonard WJ (2013) Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38(1):13–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhou W, Zhang F, Aune TM (2003) Either IL-2 or IL-12 is sufficient to direct Th1 differentiation by nonobese diabetic T cells. J Immunol 170(2):735–740

    Article  CAS  PubMed  Google Scholar 

  58. Cote-Sierra J, Foucras G, Guo L, Chiodetti L, Young HA, Hu-Li J et al (2004) Interleukin 2 plays a central role in Th2 differentiation. Proc Natl Acad Sci U S A 101(11):3880–3885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. de la Rosa M, Rutz S, Dorninger H, Scheffold A (2004) Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol 34(9):2480–2488

    Article  PubMed  CAS  Google Scholar 

  60. Yang XP, Ghoreschi K, Steward-Tharp SM, Rodriguez-Canales J, Zhu J, Grainger JR et al (2011) Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 12(3):247–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS, Lund FE et al (2012) Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36(5):847–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Boyman O, Sprent J (2012) The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 12(3):180–190

    CAS  PubMed  Google Scholar 

  63. Ray JP, Staron MM, Shyer JA, Ho PC, Marshall HD, Gray SM 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 43(4):690–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Oestreich KJ, Read KA, Gilbertson SE, Hough KP, McDonald PW, Krishnamoorthy V et al (2014) Bcl-6 directly represses the gene program of the glycolysis pathway. Nat Immunol 15(10):957–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. von Freeden-Jeffry U, Solvason N, Howard M, Murray R (1997) The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression. Immunity 7(1):147–154

    Article  Google Scholar 

  66. Dunkle A, Dzhagalov I, He YW (2011) Cytokine-dependent and cytokine-independent roles for Mcl-1: genetic evidence for multiple mechanisms by which Mcl-1 promotes survival in primary T lymphocytes. Cell Death Dis 2:e214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jacobs SR, Michalek RD, Rathmell JC (2010) IL-7 is essential for homeostatic control of T cell metabolism in vivo. J Immunol 184(7):3461–3469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yang K, Neale G, Green DR, He W, Chi H (2011) The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol 12(9):888–897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E et al (2012) Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36(1):68–78

    Article  PubMed  CAS  Google Scholar 

  70. O’Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, Buck MD et al (2014) Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41(1):75–88

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Cui G, Staron MM, Gray SM, Ho PC, Amezquita RA, Wu J et al (2015) IL-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T cell longevity. Cell 161(4):750–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Berard M, Brandt K, Bulfone-Paus S, Tough DF (2003) IL-15 promotes the survival of naive and memory phenotype CD8+ T cells. J Immunol 170(10):5018–5026

    Article  CAS  PubMed  Google Scholar 

  73. Richer MJ, Pewe LL, Hancox LS, Hartwig SM, Varga SM, Harty JT (2015) Inflammatory IL-15 is required for optimal memory T cell responses. J Clin Invest 125(9):3477–3490

    Article  PubMed  PubMed Central  Google Scholar 

  74. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS et al (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460(7251):103–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Arneja A, Johnson H, Gabrovsek L, Lauffenburger DA, White FM (2014) Qualitatively different T cell phenotypic responses to IL-2 versus IL-15 are unified by identical dependences on receptor signal strength and duration. J Immunol 192(1):123–135

    Article  CAS  PubMed  Google Scholar 

  76. Dang CV (2012) MYC on the path to cancer. Cell 149(1):22–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zeller KI, Zhao X, Lee CW, Chiu KP, Yao F, Yustein JT et al (2006) Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci U S A 103(47):17834–17839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB et al (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133(6):1106–1117

    Article  CAS  PubMed  Google Scholar 

  79. Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W et al (2012) c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151(1):68–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE et al (2012) Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151(1):56–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Thomas LR, Tansey WP (2011) Proteolytic control of the oncoprotein transcription factor Myc. Adv Cancer Res 110:77–106

    Article  CAS  PubMed  Google Scholar 

  82. Preston GC, Sinclair LV, Kaskar A, Hukelmann JL, Navarro MN, Ferrero I et al (2015) Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes. EMBO J 34(15):2008–2024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mognol GP, de Araujo-Souza PS, Robbs BK, Teixeira LK, Viola JP (2012) Transcriptional regulation of the c-Myc promoter by NFAT1 involves negative and positive NFAT-responsive elements. Cell Cycle 11(5):1014–1028

    Article  CAS  PubMed  Google Scholar 

  84. Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA et al (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25(14):6225–6234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Palazon A, Goldrath AW, Nizet V, Johnson RS (2014) HIF transcription factors, inflammation, and immunity. Immunity 41(4):518–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang R, Green DR (2012) Metabolic checkpoints in activated T cells. Nat Immunol 13(10):907–915

    Article  CAS  PubMed  Google Scholar 

  87. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y et al (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C et al (2005) TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. J Immunol 174(12):7592–7599

    Article  CAS  PubMed  Google Scholar 

  89. Wang H, Flach H, Onizawa M, Wei L, McManus MT, Weiss A (2014) Negative regulation of Hif1a expression and TH17 differentiation by the hypoxia-regulated microRNA miR-210. Nat Immunol 15(4):393–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N (2001) IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19:623–655

    Article  CAS  PubMed  Google Scholar 

  91. Huber M, Lohoff M (2014) IRF4 at the crossroads of effector T-cell fate decision. Eur J Immunol 44(7):1886–1895

    Article  CAS  PubMed  Google Scholar 

  92. Lohoff M, Mittrucker HW, Prechtl S, Bischof S, Sommer F, Kock S et al (2002) Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc Natl Acad Sci U S A 99(18):11808–11812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N et al (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33(2):192–202

    Article  CAS  PubMed  Google Scholar 

  94. Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P et al (2007) The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8(9):958–966

    Article  PubMed  CAS  Google Scholar 

  95. Kwon H, Thierry-Mieg D, Thierry-Mieg J, Kim HP, Oh J, Tunyaplin C et al (2009) Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31(6):941–952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M et al (2011) The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 12(4):304–311

    Article  CAS  PubMed  Google Scholar 

  97. Yao S, Buzo BF, Pham D, Jiang L, Taparowsky EJ, Kaplan MH et al (2013) Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation. Immunity 39(5):833–845

    Article  CAS  PubMed  Google Scholar 

  98. Grusdat M, McIlwain DR, Xu HC, Pozdeev VI, Knievel J, Crome SQ et al (2014) IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV. Cell Death Differ 21(7):1050–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Li P, Spolski R, Liao W, Wang L, Murphy TL, Murphy KM et al (2012) BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature 490(7421):543–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Glasmacher E, Agrawal S, Chang AB, Murphy TL, Zeng W, Vander Lugt B et al (2012) A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. Science 338(6109):975–980

    Article  CAS  PubMed  Google Scholar 

  101. Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F et al (2012) A validated regulatory network for Th17 cell specification. Cell 151(2):289–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Nayar R, Enos M, Prince A, Shin H, Hemmers S, Jiang JK et al (2012) TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation. Proc Natl Acad Sci U S A 109(41):E2794–E2802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Grumont RJ, Gerondakis S (2000) Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear factor kappaB. J Exp Med 191(8):1281–1292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nayar R, Schutten E, Bautista B, Daniels K, Prince AL, Enos M et al (2014) Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection. J Immunol 192(12):5881–5893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Crotty S, Johnston RJ, Schoenberger SP (2010) Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol 11(2):114–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Beaulieu AM, Sant’Angelo DB (2011) The BTB-ZF family of transcription factors: key regulators of lineage commitment and effector function development in the immune system. J Immunol 187(6):2841–2847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z et al (2013) Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest 123(10):4479–4488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Man K, Kallies A (2014) Bcl-6 gets T cells off the sugar. Nat Immunol 15(10):904–905

    Article  CAS  PubMed  Google Scholar 

  109. Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL et al (2009) The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31(3):457–468

    Article  CAS  PubMed  Google Scholar 

  110. Pipkin ME, Sacks JA, Cruz-Guilloty F, Lichtenheld MG, Bevan MJ, Rao A (2010) Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32(1):79–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Oestreich KJ, Mohn SE, Weinmann AS (2012) Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat Immunol 13(4):405–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chang JT, Wherry EJ, Goldrath AW (2014) Molecular regulation of effector and memory T cell differentiation. Nat Immunol 15(12):1104–1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109(9):1125–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Yang W, Bai Y, Xiong Y, Zhang J, Chen S, Zheng X et al (2016) Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531(7596):651–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Egawa T, Littman DR (2011) Transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene. Proc Natl Acad Sci U S A 108(36):14873–14878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Jonsson H, Peng SL (2005) Forkhead transcription factors in immunology. Cell Mol Life Sci 62(4):397–409

    Article  CAS  PubMed  Google Scholar 

  117. Feng X, Wang H, Takata H, Day TJ, Willen J, Hu H (2011) Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells. Nat Immunol 12(6):544–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wei H, Geng J, Shi B, Liu Z, Wang YH, Stevens AC et al (2016) Cutting edge: Foxp1 controls naive CD8+ T cell quiescence by simultaneously repressing key pathways in cellular metabolism and cell cycle progression. J Immunol 196:3537–3541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bopp T, Palmetshofer A, Serfling E, Heib V, Schmitt S, Richter C et al (2005) NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells. J Exp Med 201(2):181–187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Huh JR, Leung MW, Huang P, Ryan DA, Krout MR, Malapaka RR et al (2011) Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 472(7344):486–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Xiao S, Yosef N, Yang J, Wang Y, Zhou L, Zhu C et al (2014) Small-molecule RORgammat antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40(4):477–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR et al (2008) Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci U S A 105(50):19579–19586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM et al (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146(6):904–917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA et al (2011) Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A 108(40):16669–16674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bandukwala HS, Gagnon J, Togher S, Greenbaum JA, Lamperti ED, Parr NJ et al (2012) Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc Natl Acad Sci U S A 109(36):14532–14537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zirath H, Frenzel A, Oliynyk G, Segerstrom L, Westermark UK, Larsson K et al (2013) MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells. Proc Natl Acad Sci U S A 110(25):10258–10263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Touzot M, Soulillou JP, Dantal J (2012) Mechanistic target of rapamycin inhibitors in solid organ transplantation: from benchside to clinical use. Curr Opin Organ Transplant 17(6):626–633

    Article  CAS  PubMed  Google Scholar 

  128. Powell JD, Lerner CG, Schwartz RH (1999) Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol 162(5):2775–2784

    CAS  PubMed  Google Scholar 

  129. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159–168

    Article  CAS  PubMed  Google Scholar 

  130. Turner AP, Shaffer VO, Araki K, Martens C, Turner PL, Gangappa S et al (2011) Sirolimus enhances the magnitude and quality of viral-specific CD8+ T-cell responses to vaccinia virus vaccination in rhesus macaques. Am J Transplant 11(3):613–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y et al (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284(12):8023–8032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D et al (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7(2):e38

    Article  PubMed  CAS  Google Scholar 

  133. Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162(6):1229–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R et al (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162(6):1217–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We apologize to our colleagues whose work was not cited, due to space limitation. Supported by the National Scientific Foundation of China (C3140851), 973 Program (2013CB530505), and Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST to X.P.Y.

Author information

Authors and Affiliations

  1. Department of Immunology, School of Basic Medicine, Tongji Medical School, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China, 430030

    Jinxia Zhang, Guoyu Bi, Yu Xia, Pingfei Li, Xiaofei Deng, Zhengping Wei & Xiang-Ping Yang

Authors
  1. Jinxia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guoyu Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pingfei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaofei Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhengping Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiang-Ping Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiang-Ping Yang .

Editor information

Editors and Affiliations

  1. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University, Shanghai, China

    Bin Li

  2. School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Fan Pan

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Zhang, J. et al. (2017). Transcriptional Regulation of T Cell Metabolism Reprograming. In: Li, B., Pan, F. (eds) Immune Metabolism in Health and Tumor. Advances in Experimental Medicine and Biology, vol 1011. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-1170-6_3

Download citation

Publish with us

Policies and ethics

Search

Navigation