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Metabolism as a guiding force for immunity

Nature Cell Biology volume 21, pages 85–93 (2019)Cite this article

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Abstract

Recent studies indicate that cellular metabolism plays a key role in supporting immune cell maintenance and development. Here, we review how metabolism guides immune cell activation and differentiation to distinct cellular states, and how differential regulation of metabolism allows for context-dependent support during activation and lineage commitment. We discuss emerging principles of metabolic support of immune cell function in physiology and disease, as well as their general relevance to the field of cell biology.

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Fig. 1: Distinct oxidative metabolism profiles differentially support classical and alternative activation.
Fig. 2: Three examples of how paracrine metabolic coupling regulates interactions between macrophages and parenchymal cells.
Fig. 3: Metabolism guides T cell differentiation throughout its life cycle.

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References

  1. Geltink, R. I. K., Kyle, R. L. & Pearce, E. L. Unraveling the complex interplay between T cell metabolism and function. Annu. Rev. Immunol. 36, 461–488 (2018).

    Article  CAS  PubMed  Google Scholar 

  2. Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Murray, P. J. & Wynn, T. A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723–737 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ginhoux, F., Schultze, J. L., Murray, P. J., Ochando, J. & Biswas, S. K. New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat. Immunol. 17, 34–40 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. O’Neill, L. A. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15–23 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Fukuzumi, M., Shinomiya, H., Shimizu, Y., Ohishi, K. & Utsumi, S. Endotoxin-induced enhancement of glucose influx into murine peritoneal macrophages via GLUT1. Infect. Immun. 64, 108–112 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chandel, N. S. in Navigating Metabolism, Vol. 1, Edn 1 (ed. N. S. Chandel) 23–35 (Cold Spring Harb. Lab. Press, New York, 2015).

  8. Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Doughty, C. A. et al. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood 107, 4458–4465 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Donnelly, R. P. et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J. Immunol. 193, 4477–4484 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rodriguez-Prados, J. C. et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J. Immunol. 185, 605–614 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Palsson-McDermott, E. M. et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab. 21, 65–80 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kornberg, M. D. et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449–453 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Thwe, P. M. et al. Cell-intrinsic glycogen metabolism supports early glycolytic reprogramming required for dendritic cell immune responses. Cell Metab. 26, 558–567 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ip, W. K. E., Hoshi, N., Shouval, D. S., Snapper, S. & Medzhitov, R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513–519 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zigmond, E. et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 40, 720–733 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Drapier, J. C. & Hibbs, J. B. Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J. Immunol. 140, 2829–2838 (1988).

    CAS  PubMed  Google Scholar 

  20. 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 

  21. Bogdan, C. Nitric oxide and the immune response. Nat. Immunol. 2, 907–916 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Garaude, J. et al. Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense. Nat. Immunol. 17, 1037–1045 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Michelucci, A. et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc. Natl Acad. Sci. USA 110, 7820–7825 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature 556, 501–504 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yamamoto, M. et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature 430, 218–222 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Battino, M. et al. Nrf2 as regulator of innate immunity: A molecular Swiss army knife! Biotechnol. Adv. 36, 358–370 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. Luan, H. H. & Medzhitov, R. Food fight: role of itaconate and other metabolites in antimicrobial defense. Cell Metab. 24, 379–387 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Duque-Correa, M. A. et al. Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas. Proc. Natl Acad. Sci. USA 111, 4024–4032 (2014).

    Article  CAS  Google Scholar 

  34. Qualls, J. E. et al. Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. Cell Host Microbe 12, 313–323 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gao, Z. et al. Mitochondrial dynamics controls anti-tumour innate immunity by regulating CHIP-IRF1 axis stability. Nat. Commun. 8, 1805 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. 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 

  38. Wolf, A. J. et al. Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell 166, 624–636 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhong, Z. et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560, 198–203 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sanman, L. E. et al. Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. eLife 5, e13663 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Gross, C. J. et al. K+ efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Immunity 45, 761–773 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Dang, E. V., McDonald, J. G., Russell, D. W. & Cyster, J. G. Oxysterol restraint of cholesterol synthesis prevents AIM2 inflammasome activation. Cell 171, 1057–1071 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Reboldi, A. et al. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345, 679–684 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Vats, D. et al. Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation. Cell Metab. 4, 13–24 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Covarrubias, A. J. et al. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. eLife 5, e11612 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Huang, S. C. et al. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 45, 817–830 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cader, M. Z. et al. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat. Immunol. 17, 1046–1056 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Divakaruni, A. S. et al. Etomoxir inhibits macrophage polarization by disrupting CoA homeostasis. Cell Metab. 28, 490–503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nomura, M. et al. Fatty acid oxidation in macrophage polarization. Nat. Immunol. 17, 216–217 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu, P. S. et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).

    Article  CAS  PubMed  Google Scholar 

  51. Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Amit, I., Winter, D. R. & Jung, S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol. 17, 18–25 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Gautier, E. L. et al. Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J. Exp. Med. 211, 1525–1531 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Artyomov, M. N., Sergushichev, A. & Schilling, J. D. Integrating immunometabolism and macrophage diversity. Semin. Immunol. 28, 417–424 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dröge, W., Eck, H. P., Gmünder, H. & Mihm, S. Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Am. J. Med. 91, 140S–144S (1991).

    Article  PubMed  Google Scholar 

  56. Munn, D. H. & Mellor, A. L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 34, 137–143 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Pesce, J. T. et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 5, e1000371 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Murray, P. J. Amino acid auxotrophy as a system of immunological control nodes. Nat. Immunol. 17, 132–139 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wenes, M. et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. 24, 701–715 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Heitmann, L. et al. The IL-13/IL-4Rα axis is involved in tuberculosis-associated pathology. J. Pathol. 234, 338–350 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Carmona-Fontaine, C. et al. Metabolic origins of spatial organization in the tumor microenvironment. Proc. Natl Acad. Sci. USA 114, 2934–2939 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kumar, B. V., Connors, T. J. & Farber, D. L. Human T cell development, localization, and function throughout life. Immunity 48, 202–213 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rothenberg, E. V. Transcriptional control of early T and B cell developmental choices. Annu. Rev. Immunol. 32, 283–321 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. O’Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Puleston, D. J., Villa, M. & Pearce, E. L. Ancillary activity: beyond core metabolism in immune cells. Cell Metab. 26, 131–141 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Andrejeva, G. & Rathmell, J. C. Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metab. 26, 49–70 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ciofani, M. & Zuniga-Pflucker, J. C. Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat. Immunol. 6, 881–888 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Laky, K., Evans, S., Perez-Diez, A. & Fowlkes, B. J. Notch signaling regulates antigen sensitivity of naive CD4+ T cells by tuning co-stimulation. Immunity 42, 80–94 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Swamy, M. et al. Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat. Immunol. 17, 712–720 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Boudil, A. et al. IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte beta-selection. Nat. Immunol. 16, 397–405 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zeng, H. et al. Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Sci. Adv. 4, eaar5701 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Yang, K. et al. Metabolic signaling directs the reciprocal lineage decisions of αβ and γδ Tcells. Sci. Immunol. 3, eaas9818 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Mendoza, A. et al. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature 546, 158–161 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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 

  77. Zhang, S. et al. Newly generated CD4+ T cells acquire metabolic quiescence after thymic egress. J. Immunol. 200, 1064–1077 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Brownlie, R. J. & Zamoyska, R. T cell receptor signalling networks: branched, diversified and bounded. Nat. Rev. Immunol. 13, 257–269 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Molnar, E. et al. Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering. J. Biol. Chem. 287, 42664–42674 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Swamy, M. et al. A cholesterol-based allostery model of T cell receptor phosphorylation. Immunity 44, 1091–1101 (2016).

    Article  CAS  PubMed  Google Scholar 

  82. Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 14, 489–499 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang, F., Beck-Garcia, K., Zorzin, C., Schamel, W. W. & Davis, M. M. Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol. Nat. Immunol. 17, 844–850 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yang, W. et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531, 651–655 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Macintyre, A. N. et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61–72 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chang, C. H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Menk, A. V. et al. Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep. 22, 1509–1521 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tan, H. et al. Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation. Immunity 46, 488–503 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Varanasi, S. K., Jaggi, U., Hay, N. & Rouse, B. T. Hexokinase II may be dispensable for CD4 T cell responses against a virus infection. PLoS ONE 13, e0191533 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Mehta, M. M. et al. Hexokinase 2 is dispensable for T cell-dependent immunity. Cancer Metab. 6, 10 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Buck, M. D., O’Sullivan, D. & Pearce, E. L. T cell metabolism drives immunity. J. Exp. Med. 212, 1345–1360 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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 

  94. Sinclair, L. V. et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14, 500–508 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Loftus, R. M. et al. Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice. Nat. Commun. 9, 2341 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Geiger, R. et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ma, E. H. et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 25, 345–357 (2017).

    Article  CAS  PubMed  Google Scholar 

  98. Miyajima, M. et al. Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior. Nat. Immunol. 12, 1342–1352 (2017).

    Article  CAS  Google Scholar 

  99. Yang, K. et al. T Cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39, 1043–1056 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ron-Harel, N. et al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab. 24, 104–117 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tarasenko, T. N. et al. Cytochrome c oxidase activity is a metabolic checkpoint that regulates cell fate decisions during T cell activation and differentiation. Cell Metab. 25, 1254–1268 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Milasta, S. et al. Apoptosis-inducing-factor-dependent mitochondrial function is required for T cell but not B cell function. Immunity 44, 88–102 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mak, T. W. et al. Glutathione primes T cell metabolism for inflammation. Immunity 46, 675–689 (2017).

    Article  CAS  PubMed  Google Scholar 

  105. Zeng, H. & Chi, H. Metabolic control of regulatory T cell development and function. Trends Immunol. 36, 3–12 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Kolev, M. et al. Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity 42, 1033–1047 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Shi, L. Z. et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med. 20, 1327–1333 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Santori, F. R. et al. Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab. 21, 286–298 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wang, C. et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163, 1413–1427 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Xu, T. et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature 548, 228–233 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Klysz, D. et al. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8, ra97 (2015).

    Article  PubMed  CAS  Google Scholar 

  113. Metzler, B., Gfeller, P. & Guinet, E. Restricting glutamine or glutamine-dependent purine and pyrimidine syntheses promotes human T cells with high FOXP3 expression and regulatory properties. J. Immunol. 196, 3618–3630 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Tyrakis, P. A. et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chatterjee, S. et al. CD38-NAD+ axis regulates immunotherapeutic anti-tumor T cell response. Cell Metab. 27, 85–100 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Chisolm, D. A. et al. CCCTC-binding factor translates interleukin 2- and α-ketoglutarate-sensitive metabolic changes in T cells into context-dependent gene programs. Immunity 47, 251–267 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Howie, D. et al. Foxp3 drives oxidative phosphorylation and protection from lipotoxicity. JCI Insight 2, e89160 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Gerriets, V. A. et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17, 1459–1466 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Procaccini, C. et al. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity 44, 406–421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. De Rosa, V. et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat. Immunol. 16, 1174–1184 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chapman, N. M. et al. mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis. Nat. Commun. 9, 2095 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499, 485–490 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yang, K. et al. Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature 548, 602–606 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. He, N. et al. Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc. Natl Acad. Sci. USA 114, 12542–12547 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Raud, B. et al. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab. (2018).

  128. Kespohl, M. et al. The microbial metabolite butyrate induces expression of Th1-associated factors in CD4+ T cells. Front. Immunol. 8, 1036 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Mizuno, M., Noto, D., Kaga, N., Chiba, A. & Miyake, S. The dual role of short fatty acid chains in the pathogenesis of autoimmune disease models. PLoS ONE 12, e0173032 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Klein Geltink, R. I. et al. Mitochondrial priming by CD28. Cell 171, 385–397 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cui, G. et al. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T cell longevity. Cell 161, 750–761 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ma, R. et al. A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8. Nat. Cell Biol. 20, 21–27 (2018).

    Article  CAS  PubMed  Google Scholar 

  134. Phan, A. T. et al. Constitutive glycolytic metabolism supports CD8+ T cell effector memory differentiation during viral infection. Immunity 45, 1024–1037 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Bantug, G. R. et al. Mitochondria-endoplasmic reticulum contact sites function as immunometabolic hubs that orchestrate the rapid recall response of memory CD8+ T cells. Immunity 48, 542–555 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).

    Article  PubMed  CAS  Google Scholar 

  137. Verbist, K. C. et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532, 389–393 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Pollizzi, K. N. et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8+ T cell differentiation. Nat. Immunol. 17, 704–711 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Chen, Y. H. et al. Asymmetric PI3K activity in lymphocytes organized by a PI3K-mediated polarity pathway. Cell Rep. 22, 860–868 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lin, W. H. et al. Asymmetric PI3K signaling driving developmental and regenerative cell fate bifurcation. Cell Rep. 13, 2203–2218 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Byles, V. et al. The TSC-mTOR pathway regulates macrophage polarization. Nat. Commun. 4, 2834 (2013).

    Article  PubMed  CAS  Google Scholar 

  142. Linke, M. et al. Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression. Nat. Immunol. 18, 293–302 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Yin, Y. et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl Med. 7, 274ra218 (2015).

    Article  CAS  Google Scholar 

  149. Shen, Y. et al. Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nat. Immunol. 18, 1025–1034 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Yang, Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl Med. 8, 331ra338 (2016).

    Google Scholar 

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Acknowledgements

J.J. was supported by the British Society for Immunology; H.Z. by Mayo Foundation Center for Clinical and Translational Science (CCATS) and Lupus Link Minnesota; and T.H. by NIH grant R01AI102964.

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Authors and Affiliations

  1. Department of Genetics & Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Jonathan Jung & Tiffany Horng

  2. School of Medicine, University of Glasgow, Glasgow, UK

    Jonathan Jung

  3. Division of Rheumatology, Mayo Clinic, Rochester, MN, USA

    Hu Zeng

  4. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Hu Zeng

  5. ShanghaiTech University, Shanghai, China

    Tiffany Horng

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  1. Jonathan Jung
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Correspondence to Hu Zeng or Tiffany Horng.

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Jung, J., Zeng, H. & Horng, T. Metabolism as a guiding force for immunity. Nat Cell Biol 21, 85–93 (2019). https://doi.org/10.1038/s41556-018-0217-x

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