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  • Review Article
  • Published:

Dendritic cell metabolism

Nature Reviews Immunology volume 15, pages 18–29 (2015)Cite this article

Subjects

Key Points

  • This Review provides an introduction to dendritic cell subsets and biology, and the reasons for studying the metabolism of these cells.

  • We discuss the role of different metabolic pathways in dendritic cell development and in their steady-state biology, and explain how metabolic switches underpin dendritic cell activation.

  • We explain how signalling by intracellular and extracellular metabolites regulates dendritic cell biology.

  • Finally, we discuss the reciprocal roles of metabolism and pathways for sensing danger in regulating dendritic cell responses.

Abstract

The past 15 years have seen enormous advances in our understanding of the receptor and signalling systems that allow dendritic cells (DCs) to respond to pathogens or other danger signals and initiate innate and adaptive immune responses. We are now beginning to appreciate that many of these pathways not only stimulate changes in the expression of genes that control DC immune functions, but also affect metabolic pathways, thereby integrating the cellular requirements of the activation process. In this Review, we focus on this relatively new area of research and attempt to describe an integrated view of DC immunometabolism.

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Figure 1: Changes in dendritic cell metabolism through development, quiescence and activation.
Figure 2: Toll-like receptor signalling integrates endoplasmic reticulum stress and changes in metabolism to support activation.
Figure 3: Mitochondria are foci for the integration of metabolism and innate responses.

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References

  1. Satpathy, A. T., Wu, X., Albring, J. C. & Murphy, K. M. Re(de)fining the dendritic cell lineage. Nature Immunol. 13, 1145–1154 (2012).

    Article  CAS  Google Scholar 

  2. Hemmi, H. & Akira, S. TLR signalling and the function of dendritic cells. Chem. Immunol. Allergy 86, 120–135 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Osorio, F. & Reis e Sousa, C. Myeloid C-type lectin receptors in pathogen recognition and host defense. Immunity 34, 651–664 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Pearce, E. L., Poffenberger, M. C., Chang, C. H. & Jones, R. G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. O'Neill, L. A. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Pollizzi, K. N. & Powell, J. D. Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nature Rev. Immunol. 14, 435–446 (2014).

    Article  CAS  Google Scholar 

  8. Everts, B. & Pearce, E. J. Metabolic control of dendritic cell activation and function: recent advances and clinical implications. Frontiers Immunol. 5, 203 (2014).

    Google Scholar 

  9. McGettrick, A. F. & O'Neill, L. A. How metabolism generates signals during innate immunity and inflammation. J. Biol. Chem. 288, 22893–22898 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Le Naour, F. et al. Profiling changes in gene expression during differentiation and maturation of monocyte-derived dendritic cells using both oligonucleotide microarrays and proteomics. J. Biol. Chem. 276, 17920–17931 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Ishikawa, F. et al. The developmental program of human dendritic cells is operated independently of conventional myeloid and lymphoid pathways. Blood 110, 3591–3660 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zaccagnino, P. et al. An active mitochondrial biogenesis occurs during dendritic cell differentiation. Int. J. Biochem. Cell Biol. 44, 1962–1969 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Del Prete, A. et al. Role of mitochondria and reactive oxygen species in dendritic cell differentiation and functions. Free Radic. Biol. Med. 44, 1443–1451 (2008). This is an excellent review of some less well-appreciated aspects of mitochondrial biology that relate to DC function.

    Article  CAS  PubMed  Google Scholar 

  14. Rehman, A. et al. Role of fatty-acid synthesis in dendritic cell generation and function. J. Immunol. 190, 4640–4649 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hackstein, H. et al. Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood 101, 4457–4463 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Sathaliyawala, T. et al. Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity 33, 597–606 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Woltman, A. M. et al. Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression. Blood 101, 1439–1445 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Haidinger, M. et al. A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation. J. Immunol. 185, 3919–3931 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Ohtani, M. et al. Cutting edge: mTORC1 in intestinal CD11c+ CD11b+ dendritic cells regulates intestinal homeostasis by promoting IL-10 production. J. Immunol. 188, 4736–4740 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Kellersch, B. & Brocker, T. Langerhans cell homeostasis in mice is dependent on mTORC1 but not mTORC2 function. Blood 121, 298–307 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Pan, H. et al. Critical role of the tumor suppressor tuberous sclerosis complex 1 in dendritic cell activation of CD4 T cells by promoting MHC class II expression via IRF4 and CIITA. J. Immunol. 191, 699–707 (2013). References 17 and 22 show how the deletion of TSC1 results in metabolic dysregulation with marked effects on DC biology.

    Article  CAS  PubMed  Google Scholar 

  23. Wang, Y. et al. Tuberous sclerosis 1 (Tsc1)-dependent metabolic checkpoint controls development of dendritic cells. Proc. Natl Acad. Sci. USA 110, E4894–E4903 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. KC, W. et al. L-Myc expression by dendritic cells is required for optimal T-cell priming. Nature 507, 243–247 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Li, F. et al. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol. Cell. Biol. 25, 6225–6234 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wahlstrom, T. & Henriksson, M. A. Impact of MYC in regulation of tumor cell metabolism. Biochim. Biophys. Acta http://dx.doi.org/10.1016/j.bbagrm.2014.07.004 (2014).

  28. Krawczyk, C. M. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115, 4742–4749 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. O'Sullivan, D. et al. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 44, 75–88 (2014).

    Article  CAS  Google Scholar 

  30. Palsson-McDermott, E. M. & O'Neill, L. A. The Warburg effect then and now: from cancer to inflammatory diseases. BioEssays 35, 965–973 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Jantsch, J. et al. Hypoxia and hypoxia-inducible factor-1α modulate lipopolysaccharide-induced dendritic cell activation and function. J. Immunol. 180, 4697–4705 (2008). References 28 and 31 demonstrate the importance of glycolysis for supporting DC activation in response to TLR agonists.

    Article  CAS  PubMed  Google Scholar 

  32. Gerencser, A. A. et al. Quantitative microplate-based respirometry with correction for oxygen diffusion. Anal. Chem. 81, 6868–6878 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Everts, B. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKε supports the anabolic demands of dendritic cell activation. Nature Immunol. 15, 323–332 (2014). This paper shows that the increased requirement for glucose in activated DCs is linked to a need to synthesize more fatty acids to support the expansion of the ER and Golgi, and to adopt a secretory state.

    Article  CAS  Google Scholar 

  34. Brand, M. D. & Nicholls, D. G. Assessing mitochondrial dysfunction in cells. Biochem. J. 435, 297–312 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Maroof, A., English, N. R., Bedford, P. A., Gabrilovich, D. I. & Knight, S. C. Developing dendritic cells become 'lacy' cells packed with fat and glycogen. Immunology 115, 473–483 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zechner, R. et al. FAT SIGNALS—lipases and lipolysis in lipid metabolism and signaling. Cell. Metab. 15, 279–291 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nagy, L., Szanto, A., Szatmari, I. & Szeles, L. Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response. Physiol. Rev. 92, 739–789 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Ibrahim, J. et al. Dendritic cell populations with different concentrations of lipid regulate tolerance and immunity in mouse and human liver. Gastroenterology 143, 1061–1072 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Herber, D. L. et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nature Med. 16, 880–886 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Ramakrishnan, R. et al. Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J. Immunol. 192, 2920–2931 (2014).

    Article  PubMed  CAS  Google Scholar 

  42. Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Reimold, A. M. et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Osorio, F. et al. The unfolded-protein-response sensor IRE-1α regulates the function of CD8α+ dendritic cells. Nature Immunol. 15, 248–257 (2014).

    Article  CAS  Google Scholar 

  45. Iwakoshi, N. N., Pypaert, M. & Glimcher, L. H. The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J. Exp. Med. 204, 2267–2275 (2007). This paper was the first to show that the UPR has a seemingly particularly crucial role in DC biology. It should be read in conjunction with reference 44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Martinon, F. & Glimcher, L. H. Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum. Curr. Opin. Immunol. 23, 35–40 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Muralidharan, S. & Mandrekar, P. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J. Leukocyte Biol. 94, 1167–1184 (2013).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Everts, B. et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120, 1422–1431 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Amiel, E. et al. Mechanistic target of rapamycin inhibition extends cellular lifespan in dendritic cells by preserving mitochondrial function. J. Immunol. 193, 2821–2830 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Quintana, A. et al. T cell activation requires mitochondrial translocation to the immunological synapse. Proc. Natl Acad. Sci. USA 104, 14418–14423 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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. USA 110, 14336–14341 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pantel, A. et al. Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol. 12, e1001759 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Cao, W. et al. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nature Immunol. 9, 1157–1164 (2008).

    Article  CAS  Google Scholar 

  54. Amiel, E. et al. Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J. Immunol. 189, 2151–2158 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Boor, P. P., Metselaar, H. J., Mancham, S., van der Laan, L. J. & Kwekkeboom, J. Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions. Clin. Exp. Immunol. 174, 389–401 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hussaarts, L. et al. Rapamycin and omega-1: mTOR-dependent and -independent Th2 skewing by human dendritic cells. Immunol. Cell Biol. 91, 486–489 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Wobben, R. et al. Role of hypoxia inducible factor-1α for interferon synthesis in mouse dendritic cells. Biol. Chem. 394, 495–505 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Spirig, R. et al. Effects of TLR agonists on the hypoxia-regulated transcription factor HIF-1α and dendritic cell maturation under normoxic conditions. PLoS ONE 5, e0010983 (2010).

    Article  PubMed  CAS  Google Scholar 

  59. Miyamoto, S., Murphy, A. N. & Brown, J. H. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 15, 521–529 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Ward, P. S. & Thompson, C. B. Signaling in control of cell growth and metabolism. Cold Spring Harb. Perspect. Biol. 4, a006783 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. John, S., Weiss, J. N. & Ribalet, B. Subcellular localization of hexokinases I and II directs the metabolic fate of glucose. PLoS ONE 6, e17674 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pawlus, M. R. & Hu, C. J. Enhanceosomes as integrators of hypoxia inducible factor (HIF) and other transcription factors in the hypoxic transcriptional response. Cell. Signall. 25, 1895–1903 (2013).

    Article  CAS  Google Scholar 

  63. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). This paper is about macrophages, but it introduces a concept that is likely to be broadly relevant to DC biology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lisi, L., Navarra, P., Feinstein, D. L. & Dello Russo, C. The mTOR kinase inhibitor rapamycin decreases iNOS mRNA stability in astrocytes. J. Neuroinflamm. 8, 1 (2011).

    Article  CAS  Google Scholar 

  65. Blasius, A. L. et al. Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. Proc. Natl Acad. Sci. USA 107, 19973–19978 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kobayashi, T. et al. The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity 41, 375–388 (2014). This paper, which focuses on B cell biology, provides mechanistic insight into the important findings on DCs reported in references 53 and 65.

    Article  CAS  PubMed  Google Scholar 

  67. Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Waickman, A. T. & Powell, J. D. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol. Rev. 249, 43–58 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Carroll, K. C., Viollet, B. & Suttles, J. AMPKα1 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling. J. Leukocyte Biol. 94, 1113–1121 (2013).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nature Rev. Mol. Cell. Biol. 13, 225–238 (2012).

    Article  CAS  Google Scholar 

  71. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Svajger, U., Obermajer, N. & Jeras, M. Dendritic cells treated with resveratrol during differentiation from monocytes gain substantial tolerogenic properties upon activation. Immunology 129, 525–535 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rangasamy, T. et al. Nuclear erythroid 2 p45-related factor 2 inhibits the maturation of murine dendritic cells by ragweed extract. Am. J. Respir. Cell. Mol. Biol. 43, 276–285 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Aw Yeang, H. X. et al. Loss of transcription factor nuclear factor-erythroid 2 (NF-E2) p45-related factor-2 (Nrf2) leads to dysregulation of immune functions, redox homeostasis, and intracellular signaling in dendritic cells. J. Biol. Chem. 287, 10556–10564 (2012).

    Article  CAS  Google Scholar 

  75. Klotz, L. et al. Peroxisome proliferator-activated receptor γ control of dendritic cell function contributes to development of CD4+ T cell anergy. J. Immunol. 178, 2122–2131 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Rubic, T. et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nature Immunol. 9, 1261–1269 (2008).

    Article  CAS  Google Scholar 

  77. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Arnoult, D., Soares, F., Tattoli, I. & Girardin, S. E. Mitochondria in innate immunity. EMBO Rep. 12, 901–910 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nature Med. 15, 1170–1178 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Singh, N. et al. Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases. J. Biol. Chem. 285, 27601–27608 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Berndt, B. E. et al. Butyrate increases IL-23 production by stimulated dendritic cells. Am. J. Physiol. Gastrointest. Liver. Physiol. 303, G1384–G1392 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gatto, D. et al. The chemotactic receptor EBI2 regulates the homeostasis, localization and immunological function of splenic dendritic cells. Nature Immunol. 14, 446–453 (2013).

    Article  CAS  Google Scholar 

  84. Manicassamy, S. et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nature Med. 15, 401–409 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hill, J. A. et al. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 29, 758–770 (2008). References 84, 85 and 86 reveal the importance of vitamin A metabolism in DCs in the induction of immune tolerance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Manicassamy, S. & Pulendran, B. Retinoic acid-dependent regulation of immune responses by dendritic cells and macrophages. Seminars Immunol. 21, 22–27 (2009).

    Article  CAS  Google Scholar 

  88. Hall, J. A., Grainger, J. R., Spencer, S. P. & Belkaid, Y. The role of retinoic acid in tolerance and immunity. Immunity 35, 13–22 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hasko, G. & Pacher, P. A2A receptors in inflammation and injury: lessons learned from transgenic animals. J. Leukocyte Biol. 83, 447–455 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Li, L. et al. Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury. J. Clin. Invest. 122, 3931–3942 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Idzko, M. et al. Nucleotides induce chemotaxis and actin polymerization in immature but not mature human dendritic cells via activation of pertussis toxin-sensitive P2y receptors. Blood 100, 925–932 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Granstein, R. D. et al. Augmentation of cutaneous immune responses by ATPγS: purinergic agonists define a novel class of immunologic adjuvants. J. Immunol. 174, 7725–7731 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Gottfried, E. et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013–2021 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Nasi, A. & Rethi, B. Disarmed by density: A glycolytic break for immunostimulatory dendritic cells? Oncoimmunology 2, e26744 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Liu, C. et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J. Biol. Chem. 284, 2811–2822 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Hoque, R., Farooq, A., Ghani, A., Gorelick, F. & Mehal, W. Z. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology 146, 1763–1774 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Goubau, D., Deddouche, S. & Reis e Sousa, C. Cytosolic sensing of viruses. Immunity 38, 855–869 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wang, X. et al. Differential requirement for the IKKβ/NF-κB signaling module in regulating TLR- versus RLR-induced Type 1 IFN expression in dendritic cells. J. Immunol. 193, 2538–2545 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122, 669–682 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Horner, S. M., Liu, H. M., Park, H. S., Briley, J. & Gale, M. Jr. Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus. Proc. Natl Acad. Sci. USA 108, 14590–14595 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. van Vliet, A. R., Verfaillie, T. & Agostinis, P. New functions of mitochondria associated membranes in cellular signaling. Biochim. Biophys. Acta 1843, 2253–2262 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Hayashi, T., Rizzuto, R., Hajnoczky, G. & Su, T. P. MAM: more than just a housekeeper. Trends Cell Biol. 19, 81–88 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lasorsa, F. M. et al. Recombinant expression of the Ca2+-sensitive aspartate/glutamate carrier increases mitochondrial ATP production in agonist-stimulated Chinese hamster ovary cells. J. Biol. Chem. 278, 38686–38692 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Koshiba, T. Mitochondrial-mediated antiviral immunity. Biochim. Biophys. Acta 1833, 225–232 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Castanier, C., Garcin, D., Vazquez, A. & Arnoult, D. Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway. EMBO Rep. 11, 133–138 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Koshiba, T., Bashiruddin, N. & Kawabata, S. Mitochondria and antiviral innate immunity. Int. J. Biochem. Mol. Biol. 2, 257–262 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Wellen, K. E. & Thompson, C. B. A two-way street: reciprocal regulation of metabolism and signalling. Nature Rev. Mol. Cell Biol. 13, 270–276 (2012). This is an important review for understanding the broader role of metabolism in cellular functions.

    Article  CAS  Google Scholar 

  109. Mills, E. & O'Neill, L. A. Succinate: a metabolic signal in inflammation. Trends Cell Biol. 24, 313–320 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Steinman, R. M. & Cohn, Z. A. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J. Exp. Med. 137, 1142–1162 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Luo, W. & Semenza, G. L. Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2, 551–556 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Hitosugi, T. et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal 2, ra73 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Lv, L. et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol. Cell 42, 719–730 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Dominy, J. E. Jr., Lee, Y., Gerhart-Hines, Z. & Puigserver, P. Nutrient-dependent regulation of PGC-1α's acetylation state and metabolic function through the enzymatic activities of Sirt1/GCN5. Biochim. Biophys. Acta 1804, 1676–1683 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yang, H., Lee, S. M., Gao, B., Zhang, J. & Fang, D. Histone deacetylase sirtuin 1 deacetylates IRF1 protein and programs dendritic cells to control Th17 protein differentiation during autoimmune inflammation. J. Biol. Chem. 288, 37256–37266 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Alvarez, Y. et al. Sirtuin 1 is a key regulator of the interleukin-12 p70/interleukin-23 balance in human dendritic cells. J. Biol. Chem. 287, 35689–35701 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Legutko, A. et al. Sirtuin 1 promotes Th2 responses and airway allergy by repressing peroxisome proliferator-activated receptor-γ activity in dendritic cells. J. Immunol. 187, 4517–4529 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Sebastian, C. et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151, 1185–1199 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhong, L. et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell 140, 280–293 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Fang, T. C. et al. Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response. J. Exp. Med. 209, 661–669 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Igarashi, K. & Katoh, Y. Metabolic aspects of epigenome: coupling of S-adenosylmethionine synthesis and gene regulation on chromatin by SAMIT module. Sub-Cell. Biochem. 61, 105–118 (2013).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors have benefitted greatly from discussions about immune cell metabolism with E. Pearce, S. Huang, E. Amiel, R. Van der Windt, D. O'Sullivan, C.-H. Chang, C. Krawczyk, R. Jones, A. Jha, E. Driggers and M. Artymov. Their research is supported by the US National Institutes of Health (E.J.P.) and the Netherlands Organization for Scientific Research (B.E.).

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Authors and Affiliations

  1. Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Edward J. Pearce

  2. Department of Parasitology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands

    Bart Everts

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  1. Edward J. Pearce
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Correspondence to Edward J. Pearce.

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Glossary

Electron transport chain

(ETC). The electron transport chain links nutrient oxidation to ATP production by oxidative phosphorylation. It consists of complexes I–V in the mitochondrial inner membrane.

Tricarboxylic acid cycle

(TCA cycle; also known as the Krebs cycle or citric acid cycle). This pathway catalyses the oxidation of acetyl-CoA (from glucose or fatty acids, or indirectly from amino acids) to generate NADH and FADH, which fuel the electron transport chain and thereby oxidative phosphorylation and ATP production. It also serves as a source of precursors for amino acid and lipid synthesis.

Bone marrow-derived DCs

(BMDCs). These monocyte-derived dendritic cells (DCs) are generated from bone marrow cultures supplemented with granulocyte–macrophage colony-stimulating factor and are used to model the behaviour of DCs that develop from monocytes under inflammatory conditions in vivo.

Spare respiratory capacity

The amount of energy generating capacity, beyond that needed for basal biology, that a cell maintains in reserve to be used when called upon.

M1 macrophages

Macrophages that have been activated by a Toll-like receptor agonist, usually in combination with interferon-γ.

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Pearce, E., Everts, B. Dendritic cell metabolism. Nat Rev Immunol 15, 18–29 (2015). https://doi.org/10.1038/nri3771

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