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Immunometabolism and natural killer cell responses

Nature Reviews Immunology volume 19, pages 282–290 (2019)Cite this article

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Abstract

Natural killer (NK) cells are lymphocytes with important roles in innate and adaptive immune responses to tumours and viral infection. However, in certain chronic diseases, including obesity and cancer, NK cell functional responses are impaired. Recently, research has highlighted the importance of NK cell metabolism in facilitating robust NK cell effector functions. This Review describes our current understanding of mouse and human NK cell metabolism and the key signalling pathways that mediate metabolic responses in NK cells. Furthermore, it explores how defects in metabolism can contribute to the generation of dysfunctional NK cells in chronic disease. Finally, the potential for new therapeutic strategies targeting cellular metabolism is discussed.

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Fig. 1: The citrate–malate shuttle.
Fig. 2: Key regulators of NK cell metabolism.
Fig. 3: Mechanisms disrupting NK cell metabolism in cancer and obesity.

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References

  1. Loftus, R. M. & Finlay, D. K. Immunometabolism: cellular metabolism turns immune regulator. J. Biol. Chem. 291, 1–10 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Campbell, K. S. & Hasegawa, J. Natural killer cell biology: an update and future directions. J. Allergy Clin. Immunol. 132, 536–544 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Caligiuri, M. A. Human natural killer cells. Blood 112, 461–469 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bjorkstrom, N. K. et al. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J. Exp. Med. 208, 13–21 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cerwenka, A. & Lanier, L. L. Natural killer cell memory in infection, inflammation and cancer. Nat. Rev. Immunol. 16, 112–123 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. O’Leary, J. G., Goodarzi, M., Drayton, D. L. & von Andrian, U. H. T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat. Immunol. 7, 507–516 (2006).

    Article  PubMed  CAS  Google Scholar 

  9. Crouse, J., Xu, H. C., Lang, P. A. & Oxenius, A. NK cells regulating T cell responses: mechanisms and outcome. Trends Immunol. 36, 49–58 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Keppel, M. P., Saucier, N., Mah, A. Y., Vogel, T. P. & Cooper, M. A. Activation-specific metabolic requirements for NK cell IFN-gamma production. J. Immunol. 194, 1954–1962 (2015). This study shows that acute activation of mouse NK cells does not result in changes in NK cell metabolism and reveals differential requirements for metabolic pathways for the function of cytokine-stimulated versus receptor-stimulated NK cells.

    Article  CAS  PubMed  Google Scholar 

  11. Marcais, A. et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat. Immunol. 15, 749–757 (2014). This study demonstrates the importance of the metabolic regulator mTORC1 for mouse NK cell development and activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Donnelly, R. P. et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J. Immunol. 193, 4477–4484 (2014). This study reveals the importance of mTORC1 and elevated rates of glycolysis and OXPHOS for cytokine-induced mouse NK cell effector function.

    Article  CAS  PubMed  Google Scholar 

  13. Keating, S. E. et al. Metabolic reprogramming supports IFN-gamma production by CD56bright NK cells. J. Immunol. 196, 2552–2560 (2016). This study is the first to show metabolic increases in cytokine-stimulated human NK cells and to link metabolism to human NK cell effector function.

    Article  CAS  PubMed  Google Scholar 

  14. Viel, S. et al. TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci. Signal. 9, ra19 (2016).

    Article  PubMed  CAS  Google Scholar 

  15. Assmann, N. et al. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat. Immunol. 18, 1197–1206 (2017). This study shows that cytokine-activated NK cells use the CMS rather than the TCA cycle to drive OXPHOS and reveals SREBP as a central regulator of NK cell metabolic and functional responses.

    Article  CAS  PubMed  Google Scholar 

  16. O’Sullivan, T. E., Johnson, L. R., Kang, H. H. & Sun, J. C. BNIP3- and BNIP3L-mediated mitophagy promotes the generation of natural killer cell memory. Immunity 43, 331–342 (2015). This study shows the importance of mitophagy in maintaining mitochondrial fitness in NK cells and for the generation NK cell memory-like cells in MCMV-infected mice.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Jensen, H., Potempa, M., Gotthardt, D. & Lanier, L. L. Cutting edge: IL-2-induced expression of the amino acid transporters SLC1A5 and CD98 is a prerequisite for NKG2D-mediated activation of human NK cells. J. Immunol. 199, 1967–1972 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Felices, M. et al. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight 3, 96219 (2018).

    Article  PubMed  Google Scholar 

  19. Salzberger, W. et al. Tissue-resident NK cells differ in their expression profile of the nutrient transporters Glut1, CD98 and CD71. PLOS ONE 13, e0201170 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Mah, A. Y. et al. Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control. JCI Insight 2, 95128 (2017). This study shows that MCMV-infected mice treated with the glycolytic inhibitor 2DG have impaired clearance of NK cell target cells and increased viral burden.

    Article  PubMed  Google Scholar 

  21. 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). This study reveals the importance of MYC and SLC7A5 in the control of mouse NK cell metabolic and functional responses.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. O’Connor, R. S. et al. The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations. Sci. Rep. 8, 6289 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Yao, C.-H. et al. Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation. PLOS Biol. 16, e2003782 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Raud, B. et al. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab. 28, 504–515 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Michelet, X. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat. Immunol. 19, 1330–1340 (2018). This study shows that NK cell metabolism and function are disrupted during obesity owing to PPAR-mediated inactivation of mTORC1 and MYC signalling.

    Article  CAS  PubMed  Google Scholar 

  26. Chiossone, L. et al. Maturation of mouse NK cells is a 4-stage developmental program. Blood 113, 5488–5496 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. The Tabula Muris Consortium et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372 (2018).

    Article  CAS  Google Scholar 

  28. Schafer, J. R. et al. Education-dependent activation of glycolysis promotes the cytolytic potency of licensed human natural killer cells. J. Allergy Clin. Immunol. 143, 346–358 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Pfeifer, C. et al. Natural killer cell education is associated with a distinct glycolytic profile. Front. Immunol. 9, 3020 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yang, C. et al. mTORC1 and mTORC2 differentially promote natural killer cell development. eLife 7, e35619 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nandagopal, N., Ali, A. K., Komal, A. K. & Lee, S. H. The critical role of IL-15-PI3K-mTOR pathway in natural killer cell effector functions. Front. Immunol. 5, 187 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Abel, A. M. et al. IQ domain-containing GTPase-activating protein 1 regulates cytoskeletal reorganization and facilitates NKG2D-mediated mechanistic target of rapamycin complex 1 activation and cytokine gene translation in natural killer cells. Front. Immunol. 9, 1168 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Wang, F. et al. Crosstalks between mTORC1 and mTORC2 variagate cytokine signaling to control NK maturation and effector function. Nat. Commun. 9, 4874 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Finlay, D. K. et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209, 2441–2453 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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 

  36. Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Collins, P. L. et al. Gene regulatory programs conferring phenotypic identities to human NK cells. Cell 176, 348–360 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Castro, W. et al. The transcription factor Rfx7 limits metabolism of NK cells and promotes their maintenance and immunity. Nat. Immunol. 19, 809–820 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B. & Lanier, L. L. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Rolf, J. et al. AMPKalpha1: a glucose sensor that controls CD8 T cell memory. Eur. J. Immunol. 43, 889–896 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Araki, K. et al. mTOR regulates memory CD8 T cell differentiation. Nature 460, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pearce, E. L. et al. Enhancing CD8 T cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schlums, H. et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42, 443–456 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lee, J. et al. Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals. Immunity 42, 431–442 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cichocki, F. et al. ARID5B regulates metabolic programming in human adaptive NK cells. J. Exp. Med. 215, 2379–2395 (2018). This study shows alterations in NK cell metabolism in adaptive human NK cells that involve epigenetic modifications and the epigenetic modifier ARID5B.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu, L. L. et al. Critical role of CD2 co-stimulation in adaptive natural killer cell responses revealed in NKG2C-deficient humans. Cell Rep. 15, 1088–1099 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Romee, R. et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl Med. 8, 357ra123 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Romee, R. et al. Cytokine activation induces human memory-like NK cells. Blood 120, 4751–4760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cooper, M. A. et al. Cytokine-induced memory-like natural killer cells. Proc. Natl Acad. Sci. USA 106, 1915–1919 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ni, J., Miller, M., Stojanovic, A., Garbi, N. & Cerwenka, A. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J. Exp. Med. 209, 2351–2365 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pahl, J. H. W. et al. CD16A activation of NK cells promotes NK cell proliferation and memory-like cytotoxicity against cancer cells. Cancer Immunol. Res. 6, 517–527 (2018).

    Article  CAS  PubMed  Google Scholar 

  52. Smith, A. G., Sheridan, P. A., Harp, J. B. & Beck, M. A. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J. Nutr. 137, 1236–1243 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Lynch, L. A. et al. Are natural killer cells protecting the metabolically healthy obese patient? Obesity 17, 601–605 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. O’Shea, D., Cawood, T. J., O’Farrelly, C. & Lynch, L. Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke. PLOS ONE 5, e8660 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Tobin, L. M. et al. NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. JCI Insight 2, 94939 (2017).

    Article  PubMed  Google Scholar 

  56. Netter, P., Anft, M. & Watzl, C. Termination of the activating NK cell immunological synapse is an active and regulated process. J. Immunol. 199, 2528–2535 (2017).

    Article  CAS  PubMed  Google Scholar 

  57. Abarca-Rojano, E. et al. Re-organization of mitochondria at the NK cell immune synapse. Immunol. Lett. 122, 18–25 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Carpen, O., Virtanen, I. & Saksela, E. Ultrastructure of human natural killer cells: nature of the cytolytic contacts in relation to cellular secretion. J. Immunol. 128, 2691–2697 (1982).

    CAS  PubMed  Google Scholar 

  59. Cong, J. et al. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression. Cell Metab. 28, 243–255 (2018).

    Article  CAS  PubMed  Google Scholar 

  60. Caras, I. et al. Evidence for immune defects in breast and lung cancer patients. Cancer Immunol. Immunother. 53, 1146–1152 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Hirayama, A. et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 69, 4918–4925 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Urasaki, Y., Heath, L. & Xu, C. W. Coupling of glucose deprivation with impaired histone H2B monoubiquitination in tumors. PLOS ONE 7, e36775 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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 

  64. 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 

  65. Potzl, J. et al. Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN-gamma and induces NK cell-dependent lymphoma control without other immunotherapies. Int. J. Cancer 140, 2125–2133 (2017).

    Article  PubMed  CAS  Google Scholar 

  66. Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Harmon, C. et al. Lactate-mediated acidification of tumor microenvironment induces apoptosis of liver-resident NK cells in colorectal liver metastasis. Cancer Immunol. Res. https://doi.org/10.1158/2326-6066.CIR-18-0481 (2018).

    Article  PubMed  Google Scholar 

  68. Massague, J. TGFbeta in cancer. Cell 134, 215–230 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ivanovic, V. et al. Elevated plasma levels of transforming growth factor-beta 1 (TGF-beta 1) in patients with advanced breast cancer: association with disease progression. Eur. J. Cancer 39, 454–461 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Zaiatz-Bittencourt, V., Finlay, D. K. & Gardiner, C. M. Canonical TGF-beta signaling pathway represses human NK cell metabolism. J. Immunol. 200, 3934–3941 (2018).

    Article  CAS  PubMed  Google Scholar 

  71. Li, D., Long, W., Huang, R., Chen, Y. & Xia, M. 27-hydroxycholesterol inhibits sterol regulatory element-binding protein 1 activation and hepatic lipid accumulation in mice. Obesity 26, 713–722 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Adams, C. M. et al. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs. J. Biol. Chem. 279, 52772–52780 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Babiker, A. et al. Elimination of cholesterol in macrophages and endothelial cells by the sterol 27-hydroxylase mechanism. Comparison with high density lipoprotein-mediated reverse cholesterol transport. J. Biol. Chem. 272, 26253–26261 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Javitt, N. B. Breast cancer and (25R)-26-hydroxycholesterol. Steroids 104, 61–64 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Wu, Q. et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 5, 637–645 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Eibinger, G. et al. On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment. Exp. Cell Res. 319, 1828–1838 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Diczfalusy, U. et al. Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide. J. Lipid Res. 50, 2258–2264 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Park, K. & Scott, A. L. Cholesterol 25-hydroxylase production by dendritic cells and macrophages is regulated by type I interferons. J. Leukoc. Biol. 88, 1081–1087 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Mondanelli, G., Ugel, S., Grohmann, U. & Bronte, V. The immune regulation in cancer by the amino acid metabolizing enzymes ARG and IDO. Curr. Opin. Pharmacol. 35, 30–39 (2017).

    Article  CAS  PubMed  Google Scholar 

  80. Munn, D. H. & Mellor, A. L. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 37, 193–207 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Frumento, G. et al. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J. Exp. Med. 196, 459–468 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Della Chiesa, M. et al. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood 108, 4118–4125 (2006).

    Article  PubMed  CAS  Google Scholar 

  83. Sinclair, L. V., Neyens, D., Ramsay, G., Taylor, P. M. & Cantrell, D. A. Single cell analysis of kynurenine and System L amino acid transport in T cells. Nat. Commun. 9, 1981 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Maus, M. V., Grupp, S. A., Porter, D. L. & June, C. H. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123, 2625–2635 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cheng, M., Chen, Y., Xiao, W., Sun, R. & Tian, Z. NK cell-based immunotherapy for malignant diseases. Cell. Mol. Immunol. 10, 230–252 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Still, E. R. & Yuneva, M. O. Hopefully devoted to Q: targeting glutamine addiction in cancer. Br. J. Cancer 116, 1375–1381 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Zhu, L., Ploessl, K., Zhou, R., Mankoff, D. & Kung, H. F. Metabolic imaging of glutamine in cancer. J. Nucl. Med. 58, 533–537 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dunphy, M. P. S. et al. In vivo PET assay of tumor glutamine flux and metabolism: in-human trial of (18)F-(2S,4R)-4-fluoroglutamine. Radiology 287, 667–675 (2018).

    Article  PubMed  Google Scholar 

  89. Lieberman, B. P. et al. PET imaging of glutaminolysis in tumors by 18F-(2S,4R)4-fluoroglutamine. J. Nucl. Med. 52, 1947–1955 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Parameswaran, R. et al. Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nat. Commun. 7, 11154 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cichocki, F. et al. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res. 77, 5664–5675 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Saetersmoen, M. L., Hammer, Q., Valamehr, B., Kaufman, D. S. & Malmberg, K. J. Off-the-shelf cell therapy with induced pluripotent stem cell-derived natural killer cells. Semin. Immunopathol. 41, 59–68 (2018).

    Article  PubMed  Google Scholar 

  93. Li, Y., Hermanson, D. L., Moriarity, B. S. & Kaufman, D. S. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23, 181–192 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Suck, G. et al. NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol. Immunother. 65, 485–492 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. 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 

  96. 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 

  97. Preston, G. C. et al. Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes. EMBO J. 34, 2008–2024 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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 

  99. 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 

  100. 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 

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Acknowledgements

The authors acknowledge funding from the following sources: European Commission (EU Framework Programme for Research and Innovation H2020, H2020 Priority Excellent Science and H2020 European Research Council) and Science Foundation Ireland to D.K.F. and Irish Cancer Society to K.L.O’B.

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Nature Reviews Immunology thanks J. Miller and other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    Katie L. O’Brien & David K. Finlay

  2. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    David K. Finlay

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O’Brien, K.L., Finlay, D.K. Immunometabolism and natural killer cell responses. Nat Rev Immunol 19, 282–290 (2019). https://doi.org/10.1038/s41577-019-0139-2

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