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Natural killer cell memory in infection, inflammation and cancer

Nature Reviews Immunology volume 16, pages 112–123 (2016)Cite this article

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Key Points

  • Emerging data provide evidence that natural killer (NK) cells can contribute to immunological memory, an activity that has traditionally been associated with T cells and B cells. Three main types of NK cell memory exist, namely hapten-specific NK cell memory, virus-specific NK cell memory and cytokine-induced NK cell memory.

  • Distinct receptor–ligand interactions and distinct cytokine milieus lead to the generation of antigen-specific memory NK cells. Cytokine-induced memory NK cells can be generated by exposure to inflammatory cytokines even in the absence of a defined antigen.

  • The different types of memory NK cells differ in terms of their tissue localization patterns. For example, hapten-specific memory NK cells reside in the liver, influenza virus-specific memory NK cells reside in the liver and lung, and mouse cytomegalovirus (MCMV)-specific NK cells and cytokine-induced memory NK cells are systemically distributed.

  • Most of our mechanistic knowledge of the signals that drive the generation of virus-specific memory NK cells originates from experiments using MCMV infection as a model system. These studies have identified LY49H as the MCMV-specific activating NK cell receptor and m157 as the cognate viral ligand recognized by LY49H.

  • The basic concepts derived from studying NK cell memory might lead to novel strategies for refining vaccination protocols to improve treatments for infectious diseases.

  • It is possible that NK cell memory activity could be exploited for cancer therapy. Lessons learned from the study of NK cell memory could help with the design of better expansion protocols for adoptive NK cell therapy, for the manufacturing of chimeric antigen receptor (CAR)-engineered NK cells and for improving NK cell-based therapies that rely on antibody-dependent cellular cytotoxicity (ADCC).

Abstract

Immunological memory can be defined as a quantitatively and qualitatively enhanced immune response upon rechallenge. For natural killer (NK) cells, two main types of memory exist. First, similarly to T cells and B cells, NK cells can exert immunological memory after encounters with stimuli such as haptens or viruses, resulting in the generation of antigen-specific memory NK cells. Second, NK cells can remember inflammatory cytokine milieus that imprint long-lasting non-antigen-specific NK cell effector function. The basic concepts derived from studying NK cell memory provide new insights about innate immunity and could lead to novel strategies to improve treatments for infectious diseases and cancer.

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Figure 1: Pathways for the generation of memory NK cells.
Figure 2: NK cell memory in HCMV-seropositive donors.
Figure 3: Potential applications of memory NK cells for tumour therapy.

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References

  1. Sun, J. C., Ugolini, S. & Vivier, E. Immunological memory within the innate immune system. EMBO J. 33, 1295–1303 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Quintin, J., Cheng, S. C., van der Meer, J. W. & Netea, M. G. Innate immune memory: towards a better understanding of host defense mechanisms. Curr. Opin. Immunol. 29, 1–7 (2014).

    CAS  PubMed  Google Scholar 

  3. O'Sullivan, T. E., Sun, J. C. & Lanier, L. L. Natural killer cell memory. Immunity 43, 634–645 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kiessling, R. Klein, E., Pross, H. & Wigzell, H. “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur. J. Immunol. 5, 117–121 (1975).

    CAS  PubMed  Google Scholar 

  5. Kiessling, R. Klein, E. & Wigzell, H. “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur. J. Immunol. 5, 112–117 (1975).

    CAS  PubMed  Google Scholar 

  6. Herberman, R. B., Nunn, M. E., Holden, H. T. & Lavrin, D. H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int. J. Cancer 16, 230–239 (1975).

    CAS  PubMed  Google Scholar 

  7. Trinchieri, G., Perussia, B., Santoli, D. & Cerottini, J. C. Human natural killer cells. Transplant Proc. 11, 807–810 (1979).

    CAS  PubMed  Google Scholar 

  8. Bezman, N. A. et al. Molecular definition of the identity and activation of natural killer cells. Nat. Immunol. 13, 1000–1009 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Vivier, E. What is natural in natural killer cells? Immunol. Lett. 107, 1–7 (2006).

    CAS  PubMed  Google Scholar 

  10. Lucas, M., Schachterle, W., Oberle, K., Aichele, P. & Diefenbach, A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26, 503–517 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lanier, L. L. Up on the tightrope: natural killer cell activation and inhibition. Nat. Immunol. 9, 495–502 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Paust, S. & von Andrian, U. H. Natural killer cell memory. Nat. Immunol. 12, 500–508 (2011).

    CAS  PubMed  Google Scholar 

  13. 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). This seminal paper reports the first observation of NK cell memory responses against haptens.

    CAS  PubMed  Google Scholar 

  14. Paust, S. et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat. Immunol. 11, 1127–1135 (2010). This important paper reveals that NK cell memory develops against haptens, influenza virus and VSV, and indicates the importance of the chemokine receptor CXCR6 in this process.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Rouzaire, P. et al. Natural killer cells and T cells induce different types of skin reactions during recall responses to haptens. Eur. J. Immunol. 42, 80–88 (2012).

    CAS  PubMed  Google Scholar 

  16. Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009). This is the first report on NK cell memory in viral infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sun, J. C., Beilke, J. N. & Lanier, L. L. Immune memory redefined: characterizing the longevity of natural killer cells. Immunol. Rev. 236, 83–94 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Gillard, G. O. et al. Thy1+ NK cells from vaccinia virus-primed mice confer protection against vaccinia virus challenge in the absence of adaptive lymphocytes. PLoS Pathog. 7, e1002141 (2011). This report dissects vaccinia virus-specific memory mediated by hepatic NK cells upon sensitization with live virus.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Abdul-Careem, M. F. et al. Genital HSV-2 infection induces short-term NK cell memory. PLoS ONE 7, e32821 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Reeves, R. K. et al. Antigen-specific NK cell memory in rhesus macaques. Nat. Immunol. 16, 927–932 (2015). This report is the first observation of NK cell memory in non-human primates.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Keppel, M. P., Yang, L. & Cooper, M. A. Murine NK cell intrinsic cytokine-induced memory-like responses are maintained following homeostatic proliferation. J. Immunol. 190, 4754–4762 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Cooper, M. A. et al. Cytokine-induced memory-like natural killer cells. Proc. Natl Acad. Sci. USA 106, 1915–1919 (2009). This seminal paper is the first to show that NK cell memory develops following the brief exposure of NK cells to IL-12, IL-15 and IL-18.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Majewska-Szczepanik, M., Paust, S., von Andrian, U. H., Askenase, P. W. & Szczepanik, M. Natural killer cell-mediated contact sensitivity develops rapidly and depends on interferon-α, interferon-γ and interleukin-12. Immunology 140, 98–110 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Brown, M. G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).

    CAS  PubMed  Google Scholar 

  26. Lee, S. H. et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat. Genet. 28, 42–45 (2001).

    CAS  PubMed  Google Scholar 

  27. Dokun, A. O. et al. Specific and nonspecific NK cell activation during virus infection. Nat. Immunol. 2, 951–956 (2001).

    CAS  PubMed  Google Scholar 

  28. 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).

    CAS  PubMed  Google Scholar 

  29. Smith, H. R. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl Acad. Sci. USA 99, 8826–8831 (2002).

    CAS  PubMed  Google Scholar 

  30. Nabekura, T. et al. Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 40, 225–234 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Orr, M. T., Murphy, W. J. & Lanier, L. L. 'Unlicensed' natural killer cells dominate the response to cytomegalovirus infection. Nat. Immunol. 11, 321–327 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Martinet, L. & Smyth, M. J. Balancing natural killer cell activation through paired receptors. Nat. Rev. Immunol. 15, 243–254 (2015).

    CAS  PubMed  Google Scholar 

  33. Guma, M. et al. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104, 3664–3671 (2004).

    CAS  PubMed  Google Scholar 

  34. Foley, B. et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood 119, 2665–2674 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lopez-Verges, S. et al. Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc. Natl Acad. Sci. USA 108, 14725–14732 (2011).

    CAS  PubMed  Google Scholar 

  36. Della Chiesa, M. et al. Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood 119, 399–410 (2012).

    CAS  PubMed  Google Scholar 

  37. Foley, B. et al. Human cytomegalovirus (CMV)-induced memory-like NKG2C+ NK cells are transplantable and expand in vivo in response to recipient CMV antigen. J. Immunol. 189, 5082–5088 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Guma, M. et al. Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 107, 3624–3631 (2006).

    CAS  PubMed  Google Scholar 

  39. Rolle, A. et al. IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion. J. Clin. Invest. 124, 5305–5316 (2014).

    PubMed  PubMed Central  Google Scholar 

  40. Beziat, V. et al. CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur. J. Immunol. 42, 447–457 (2012).

    CAS  PubMed  Google Scholar 

  41. Noyola, D. E. et al. Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK-cell subset distribution in children. Eur. J. Immunol. 42, 3256–3266 (2012).

    CAS  PubMed  Google Scholar 

  42. Beziat, V. et al. NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood 121, 2678–2688 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Goodier, M. R. et al. Rapid NK cell differentiation in a population with near-universal human cytomegalovirus infection is attenuated by NKG2C deletions. Blood 124, 2213–2222 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang, T., Scott, J. M., Hwang, I. & Kim, S. Cutting edge: antibody-dependent memory-like NK cells distinguished by FcRγ deficiency. J. Immunol. 190, 1402–1406 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 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). This important report characterizes the molecular signature of the FcεRIγ-deficient NK cell subset.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    PubMed  PubMed Central  Google Scholar 

  47. Brunetta, E. et al. Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection. AIDS 24, 27–34 (2010).

    PubMed  Google Scholar 

  48. Sun, J. C. et al. Proinflammatory cytokine signaling required for the generation of natural killer cell memory. J. Exp. Med. 209, 947–954 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sun, J. C., Ma, A. & Lanier, L. L. Cutting edge: IL-15-independent NK cell response to mouse cytomegalovirus infection. J. Immunol. 183, 2911–2914 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Madera, S. & Sun, J. C. Cutting edge: stage-specific requirement of IL-18 for antiviral NK cell expansion. J. Immunol. 194, 1408–1412 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Nabekura, T., Girard, J. P. & Lanier, L. L. IL-33 receptor ST2 amplifies the expansion of NK cells and enhances host defense during mouse cytomegalovirus infection. J. Immunol. 194, 5948–5952 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Bustamante, J. et al. Novel primary immunodeficiencies revealed by the investigation of paediatric infectious diseases. Curr. Opin. Immunol. 20, 39–48 (2008).

    CAS  PubMed  Google Scholar 

  53. Lee, S. H., Fragoso, M. F. & Biron, C. A. Cutting edge: a novel mechanism bridging innate and adaptive immunity: IL-12 induction of CD25 to form high-affinity IL-2 receptors on NK cells. J. Immunol. 189, 2712–2716 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Leong, J. W. et al. Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Biol. Blood Marrow Transplant. 20, 463–473 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kamimura, Y. & Lanier, L. L. Homeostatic control of memory cell progenitors in the natural killer cell lineage. Cell Rep. 10, 280–291 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Beaulieu, A. M., Zawislak, C. L., Nakayama, T. & Sun, J. C. The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection. Nat. Immunol. 15, 546–553 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Zawislak, C. L. et al. Stage-specific regulation of natural killer cell homeostasis and response against viral infection by microRNA-155. Proc. Natl Acad. Sci. USA 110, 6967–6972 (2013).

    CAS  PubMed  Google Scholar 

  59. Karo, J. M., Schatz, D. G. & Sun, J. C. The RAG recombinase dictates functional heterogeneity and cellular fitness in natural killer cells. Cell 159, 94–107 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Min-Oo, G., Bezman, N. A., Madera, S., Sun, J. C. & Lanier, L. L. Proapoptotic Bim regulates antigen-specific NK cell contraction and the generation of the memory NK cell pool after cytomegalovirus infection. J. Exp. Med. 211, 1289–1296 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Luetke-Eversloh, M. et al. Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in NKG2Chi natural killer cells. PLoS Pathog. 10, e1004441 (2014).

    PubMed  PubMed Central  Google Scholar 

  63. Majewska-Szczepanik, M. et al. Epicutaneous immunization with hapten-conjugated protein antigen alleviates contact sensitivity mediated by three different types of effector cells. Pharmacol. Rep. 64, 919–926 (2012).

    CAS  PubMed  Google Scholar 

  64. Peng, H. et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013). This report reveals the phenotype of the liver-resident hepatic NK cell population that mediates CHS responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Peng, H. & Tian, Z. Re-examining the origin and function of liver-resident NK cells. Trends Immunol. 36, 293–299 (2015).

    CAS  PubMed  Google Scholar 

  66. Sojka, D. K. et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife 3, e01659 (2014).

    PubMed  PubMed Central  Google Scholar 

  67. Schlums, H. et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42, 443–456 (2015). This important report characterizes the FcεRIγ-deficient NK cell subset.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Min-Oo, G. & Lanier, L. L. Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection. J. Exp. Med. 211, 2669–2680 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Nielsen, C. M. et al. Impaired NK cell responses to pertussis and H1N1 influenza vaccine antigens in human cytomegalovirus-infected individuals. J. Immunol. 194, 4657–4667 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gasteiger, G., Fan, X., Dikiy, S., Lee, S. Y. & Rudensky, A. Y. Tissue residency of innate lymphoid cells in lymphoid and non-lymphoid organs. Science 350, 981–985 (2015). This report reveals the tissue residency of NK cell subsets and ILCs.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Waggoner, S. N., Cornberg, M., Selin, L. K. & Welsh, R. M. Natural killer cells act as rheostats modulating antiviral T cells. Nature 481, 394–398 (2012).

    CAS  Google Scholar 

  72. Coudert, J. D., Scarpellino, L., Gros, F., Vivier, E. & Held, W. Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways. Blood 111, 3571–3578 (2008).

    CAS  PubMed  Google Scholar 

  73. Deng, W. et al. Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science 348, 136–139 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Miller, J. S. et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105, 3051–3057 (2005).

    CAS  PubMed  Google Scholar 

  75. Parkhurst, M. R., Riley, J. P., Dudley, M. E. & Rosenberg, S. A. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin. Cancer Res. 17, 6287–6297 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Ardolino, M. et al. Cytokine therapy reverses NK cell anergy in MHC-deficient tumors. J. Clin. Invest. 124, 4781–4794 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Huber, C. M., Doisne, J. M. & Colucci, F. IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of mismatched hematopoietic cell transplantation. Eur. J. Immunol. 45, 1727–1735 (2015).

    PubMed  PubMed Central  Google Scholar 

  78. Klingemann, H. Are natural killer cells superior CAR drivers? Oncoimmunology 3, e28147 (2014).

    PubMed  PubMed Central  Google Scholar 

  79. Abes, R., Gelize, E., Fridman, W. H. & Teillaud, J. L. Long-lasting antitumor protection by anti-CD20 antibody through cellular immune response. Blood 116, 926–934 (2010).

    CAS  PubMed  Google Scholar 

  80. Tribouley, J., Tribouley-Duret, J. & Appriou, M. [Effect of Bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni]. C. R. Seances Soc. Biol. Fil. 172, 902–904 (1978).

    CAS  PubMed  Google Scholar 

  81. van 't Wout, J. W., Poell, R. & van Furth, R. The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand. J. Immunol. 36, 713–719 (1992).

    CAS  PubMed  Google Scholar 

  82. Krieg, A. M., Love-Homan, L., Yi, A. K. & Harty, J. T. CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J. Immunol. 161, 2428–2434 (1998).

    CAS  PubMed  Google Scholar 

  83. Ishii, K. J. et al. CpG-activated Thy1.2+ dendritic cells protect against lethal Listeria monocytogenes infection. Eur. J. Immunol. 35, 2397–2405 (2005).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  85. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    PubMed  PubMed Central  Google Scholar 

  86. Yoshida, K. et al. The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory. Nat. Immunol. 16, 1034–1043 (2015).

    CAS  PubMed  Google Scholar 

  87. Koch, J., Steinle, A., Watzl, C. & Mandelboim, O. Activating natural cytotoxicity receptors of natural killer cells in cancer and infection. Trends Immunol. 34, 182–191 (2013).

    CAS  PubMed  Google Scholar 

  88. Lanier, L. L., Corliss, B., Wu, J. & Phillips, J. H. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8, 693–701 (1998).

    CAS  PubMed  Google Scholar 

  89. Orr, M. T. et al. Ly49H signaling through DAP10 is essential for optimal natural killer cell responses to mouse cytomegalovirus infection. J. Exp. Med. 206, 807–817 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Diefenbach, A. et al. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat. Immunol. 3, 1142–1149 (2002).

    CAS  PubMed  Google Scholar 

  91. Gilfillan, S., Ho, E. L., Cella, M., Yokoyama, W. M. & Colonna, M. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nat. Immunol. 3, 1150–1155 (2002).

    CAS  PubMed  Google Scholar 

  92. Ndhlovu, L. C. et al. Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 119, 3734–3743 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Gleason, M. K. et al. Tim-3 is an inducible human natural killer cell receptor that enhances interferon γ production in response to galectin-9. Blood 119, 3064–3072 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Paolino, M. et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors cordially thank A. Stojanovic and M. Correia from the Cerwenka laboratory for critically reading the manuscript and for many helpful discussions. They also thank A. Rölle, N. Jing and J. Pollmann for helping with the preparation of the figures. L.L.L. is an American Cancer Society Professor and is funded by US National Institutes of Health grants (AI066897 and AI068129). A.C. is funded by grants from the German Cancer Aid, Deutsche Krebshilfe (110442 and 111455) and from the German Research Foundation (DFG; RTG2099).

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  1. Innate Immunity Group, German Cancer Research Center/D080, 69120, Heidelberg, Germany

    Adelheid Cerwenka

  2. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, 94143, California, USA

    Lewis L. Lanier

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Correspondence to Adelheid Cerwenka.

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Cerwenka, A., Lanier, L. Natural killer cell memory in infection, inflammation and cancer. Nat Rev Immunol 16, 112–123 (2016). https://doi.org/10.1038/nri.2015.9

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