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Targeting natural killer cells and natural killer T cells in cancer

Key Points

  • Natural killer (NK) and natural killer T (NKT) cells are subsets of lymphocytes that share some phenotypical and functional similarities.

  • NK and NKT cells can rapidly respond to the presence of tumour cells and participate in antitumour immune responses.

  • Innovative anticancer therapies that are based on the manipulation of NK cells include allogeneic haematopoietic stem cell transplantation, infusion of NK cells and monoclonal antibody-based treatments.

  • The combined transfer of invariant NKT cells and α-galactosylceramide-pulsed dendritic cells induces substantial antitumour immunity in patients.

Abstract

Natural killer (NK) cells and natural killer T (NKT) cells are subsets of lymphocytes that share some phenotypical and functional similarities. Both cell types can rapidly respond to the presence of tumour cells and participate in antitumour immune responses. This has prompted interest in the development of innovative cancer therapies that are based on the manipulation of NK and NKT cells. Recent studies have highlighted how the immune reactivity of NK and NKT cells is shaped by the environment in which they develop. The rational use of these cells in cancer immunotherapies awaits a better understanding of their effector functions, migratory patterns and survival properties in humans.

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Figure 1: Recognition of tumour cells by NK cells.
Figure 2: Cancer therapies targeting NK cells.
Figure 3: Antitumour activities of iNKT cells.
Figure 4: Targeting iNKT cells for cancer therapy.

References

  1. 1

    Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Beutler, B. Innate immunity: an overview. Mol. Immunol. 40, 845–859 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675–680 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Spits, H. & Di Santo, J. P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nature Immunol. 12, 21–27 (2011).

    CAS  Article  Google Scholar 

  5. 5

    Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Oldham, R. K. & Herberman, R. B. Evaluation of cell-mediated cytotoxic reactivity against tumor associated antigens with 125I-iododeoxyuridine labeled target cells. J. Immunol. 111, 862–871 (1973).

    CAS  PubMed  Google Scholar 

  7. 7

    Herberman, R. B., Nunn, M. E. & Lavrin, D. H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int. J. Cancer 16, 216–229 (1975).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    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  Article  Google Scholar 

  9. 9

    Smyth, M. J., Hayakawa, Y., Takeda, K. & Yagita, H. New aspects of natural-killer-cell surveillance and therapy of cancer. Nature Rev. Cancer 2, 850–861 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Vesely, M. D., Kershaw, M. H., Schreiber, R. D. & Smyth, M. J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29, 235–271 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Orange, J. S. & Ballas, Z. K. Natural killer cells in human health and disease. Clin. Immunol. 118, 1–10 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Imai, K., Matsuyama, S., Miyake, S., Suga, K. & Nakachi, K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet 356, 1795–1799 (2000). One of the very few epidemiological studies to suggest a role for NK cells in the control of tumours in humans.

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Carrega, P. et al. Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56brightCD16 cells and display an impaired capability to kill tumor cells. Cancer 112, 863–875 (2008).

    Article  Google Scholar 

  14. 14

    Platonova, S. et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 71, 5412–5422 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Eckl, J. et al. Transcript signature predicts tissue NK cell content and defines renal cell carcinoma subgroups independent of TNM staging. J. Mol. Med. 90, 55–66 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Halama, N. et al. Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines. Clin. Cancer Res. 17, 678–689 (2011).

    CAS  Article  Google Scholar 

  17. 17

    Menard, C. et al. Natural killer cell IFN-γ levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res. 69, 3563–3569 (2009).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Kronenberg, M. & Gapin, L. The unconventional lifestyle of NKT cells. Nature Rev. Immunol. 2, 557–568 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Tilloy, F. et al. An invariant T cell receptor α chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted α/β T cell subpopulation in mammals. J. Exp. Med. 189, 1907–1921 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Benlagha, K., Kyin, T., Beavis, A., Teyton, L. & Bendelac, A. A thymic precursor to the NK T cell lineage. Science 296, 553–555 (2002).

    CAS  Article  Google Scholar 

  21. 21

    Gapin, L., Matsuda, J. L., Surh, C. D. & Kronenberg, M. NKT cells derive from double-positive thymocytes that are positively selected by CD1d. Nature Immunol. 2, 971–978 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Egawa, T. et al. Genetic evidence supporting selection of the Vα14i NKT cell lineage from double-positive thymocyte precursors. Immunity 22, 705–716 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Lantz, O. & Bendelac, A. An invariant T cell receptor α chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD48 T cells in mice and humans. J. Exp. Med. 180, 1097–1106 (1994).

    CAS  Article  Google Scholar 

  24. 24

    Porcelli, S., Yockey, C. E., Brenner, M. B. & Balk, S. P. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD48 α/β T cells demonstrates preferential use of several Vβ genes and an invariant TCR α chain. J. Exp. Med. 178, 1–16 (1993).

    CAS  Article  Google Scholar 

  25. 25

    Schumann, J., Voyle, R. B., Wei, B. Y. & MacDonald, H. R. Cutting edge: influence of the TCR Vβ domain on the avidity of CD1d:α-galactosylceramide binding by invariant Vα14 NKT cells. J. Immunol. 170, 5815–5819 (2003).

    Article  PubMed  Google Scholar 

  26. 26

    Wei, D. G., Curran, S. A., Savage, P. B., Teyton, L. & Bendelac, A. Mechanisms imposing the Vβ bias of Vα14 natural killer T cells and consequences for microbial glycolipid recognition. J. Exp. Med. 203, 1197–1207 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Zhou, D. et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 306, 1786–1789 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Pei, B. et al. Diverse endogenous antigens for mouse NKT cells: self-antigens that are not glycosphingolipids. J. Immunol. 186, 1348–1360 (2011). This study suggests that the self antigens recognized by NKT cells may not be exclusively glycosphingolipids.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Venkataswamy, M. M. & Porcelli, S. A. Lipid and glycolipid antigens of CD1d-restricted natural killer T cells. Semin. Immunol. 22, 68–78 (2010).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Kronenberg, M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu. Rev. Immunol. 23, 877–900 (2004).

    Article  CAS  Google Scholar 

  32. 32

    Godfrey, D. I., Pellicci, D. G. & Smyth, M. J. Immunology: the elusive NKT cell antigen — is the search over? Science 306, 1687–1689 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Bendelac, A., Savage, P. B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2006).

    Article  CAS  Google Scholar 

  34. 34

    Smyth, M. J. et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661–668 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Swann, J. B. et al. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 113, 6382–6385 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Nowak, M. et al. Defective NKT cell activation by CD1d+ TRAMP prostate tumor cells is corrected by interleukin-12 with α-galactosylceramide. PLoS ONE 5, e11311 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Bellone, M. et al. iNKT cells control mouse spontaneous carcinoma independently of tumor-specific cytotoxic T cells. PLoS ONE 5, e8646 (2010). References 34–37 suggest a tumour immunosurveillance role for NKT cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Savage, A. K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Kovalovsky, D. et al. The BTB–zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nature Immunol. 9, 1055–1064 (2008).

    CAS  Article  Google Scholar 

  40. 40

    Gascoyne, D. M. et al. The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nature Immunol. 10, 1118–1124 (2009).

    CAS  Article  Google Scholar 

  41. 41

    Kamizono, S. et al. Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J. Exp. Med. 206, 2977–2986 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Wesley, J. D., Tessmer, M. S., Chaukos, D. & Brossay, L. NK cell-like behavior of Vα14i NK T cells during MCMV infection. PLoS Pathog. 4, e1000106 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Tyznik, A. J. et al. Cutting edge: the mechanism of invariant NKT cell responses to viral danger signals. J. Immunol. 181, 4452–4456 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Brigl, M. et al. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J. Exp. Med. 208, 1163–1177 (2011). References 43–45 suggest that NKT cells can behave as innate immune cells.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Stetson, D. B. et al. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198, 1069–1076 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Matsuda, J. L. et al. Homeostasis of Vα14i NKT cells. Nature Immunol. 3, 966–974 (2002).

    CAS  Article  Google Scholar 

  48. 48

    Ranson, T. et al. IL-15 availability conditions homeostasis of peripheral natural killer T cells. Proc. Natl Acad. Sci. USA 100, 2663–2668 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Townsend, M. J. et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells. Immunity 20, 477–494 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Wingender, G., Krebs, P., Beutler, B. & Kronenberg, M. Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178-dependent and is correlated with antigenic potency. J. Immunol. 185, 2721–2729 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Carlyle, J. R. et al. Evolution of the Ly49 and Nkrp1 recognition systems. Semin. Immunol. 20, 321–330 (2008).

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Parham, P. MHC class I molecules and KIRs in human history, health and survival. Nature Rev. Immunol. 5, 201–214 (2005).

    CAS  Article  Google Scholar 

  53. 53

    Kim, S. et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Fernandez, N. C. et al. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood 105, 4416–4423 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Anfossi, N. et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity 25, 331–342 (2006). References 53–55 indicate that MHC class I recognition by NK cell inhibitory receptors contributes to the acquisition of NK cell functions.

    CAS  Article  Google Scholar 

  56. 56

    Yokoyama, W. M. & Kim, S. How do natural killer cells find self to achieve tolerance? Immunity 24, 249–257 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Raulet, D. H. & Vance, R. E. Self-tolerance of natural killer cells. Nature Rev. Immunol. 6, 520–531 (2006).

    CAS  Article  Google Scholar 

  58. 58

    Brodin, P., Karre, K. & Hoglund, P. NK cell education: not an on-off switch but a tunable rheostat. Trends Immunol. 30, 143–149 (2009).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Orr, M. T. & Lanier, L. L. Natural killer cell education and tolerance. Cell 142, 847–856 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Hoglund, P. et al. Recognition of β2-microglobulin-negative (β2m) T-cell blasts by natural killer cells from normal but not from β2m mice: nonresponsiveness controlled by β2m bone marrow in chimeric mice. Proc. Natl Acad. Sci. USA 88, 10332–10336 (1991).

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Liao, N.-S., Bix, M., Zilstra, M., Jaenish, R. & Raulet, D. MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science 253, 199–202 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

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

    CAS  Article  Google Scholar 

  63. 63

    Joncker, N. T., Fernandez, N. C., Treiner, E., Vivier, E. & Raulet, D. H. NK cell responsiveness is tuned commensurate with the number of inhibitory receptors for self-MHC class I: the rheostat model. J. Immunol. 182, 4572–4580 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Brodin, P., Lakshmikanth, T., Johansson, S., Karre, K. & Hoglund, P. The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells. Blood 113, 2434–2441 (2009).

    CAS  Article  Google Scholar 

  65. 65

    Guia, S. et al. Confinement of activating receptors at the plasma membrane controls natural killer cell tolerance. Sci. Signal. 4, ra21 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. 66

    Joncker, N. T., Shifrin, N., Delebecque, F. & Raulet, D. H. Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment. J. Exp. Med. 207, 2065–2072 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Elliott, J. M., Wahle, J. A. & Yokoyama, W. M. MHC class I-deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I-sufficient environment. J. Exp. Med. 207, 2073–2079 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Kijima, M., Gardiol, N. & Held, W. Natural killer cell mediated missing-self recognition can protect mice from primary chronic myeloid leukemia in vivo. PLoS ONE 6, e27639 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Bottino, C., Moretta, L. & Moretta, A. NK cell activating receptors and tumor recognition in humans. Curr. Top. Microbiol. Immunol. 298, 175–182 (2006).

    CAS  PubMed  Google Scholar 

  70. 70

    Moretta, A. et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu. Rev. Immunol. 19, 197–223 (2001). This review covers the discovery of activating NK cell receptors.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Bauer, S. et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Raulet, D. H. & Guerra, N. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nature Rev. Immunol. 9, 568–580 (2009).

    CAS  Article  Google Scholar 

  73. 73

    Raulet, D. H. Roles of the NKG2D immunoreceptor and its ligands. Nature Rev. Immunol. 3, 781–790 (2003).

    CAS  Article  Google Scholar 

  74. 74

    Diefenbach, A., Jamieson, A. M., Liu, S. D., Shastri, N. & Raulet, D. H. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nature Immunol. 1, 119–126 (2000).

    CAS  Article  Google Scholar 

  75. 75

    Cerwenka, A. et al. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12, 721–727 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Cosman, D. et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Carayannopoulos, L. N. et al. Ligands for murine NKG2D display heterogenous binding behavior. Eur. J. Immunol. 32, 597–605 (2002). References 74–77 report the identification of NKG2D ligands.

    CAS  Article  PubMed  Google Scholar 

  78. 78

    Guerra, N. et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28, 571–580 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Unni, A. M., Bondar, T. & Medzhitov, R. Intrinsic sensor of oncogenic transformation induces a signal for innate immunosurveillance. Proc. Natl Acad. Sci. USA 105, 1686–1691 (2008).

    CAS  Article  PubMed  Google Scholar 

  80. 80

    Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Soriani, A. et al. ATM-ATR dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK cell susceptibility and is associated with a senescent phenotype. Blood 113, 3503–3511 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Sivori, S. et al. p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J. Exp. Med. 186, 1129–1136 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Vitale, M. et al. NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis. J. Exp. Med. 187, 2065–2072 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Pende, D. et al. Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J. Exp. Med. 190, 1505–1516 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Brandt, C. S. et al. The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J. Exp. Med. 206, 1495–1503 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Li, Y., Wang, Q. & Mariuzza, R. A. Structure of the human activating natural cytotoxicity receptor NKp30 bound to its tumor cell ligand B7-H6. J. Exp. Med. 208, 703–714 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Bottino, C. et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J. Exp. Med. 198, 557–567 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Cartron, G. et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood 99, 754–758 (2002). This study reveals the importance of CD16 for monoclonal antibody therapies in humans.

    CAS  Article  Google Scholar 

  89. 89

    Veeramani, S. et al. Rituximab infusion induces NK activation in lymphoma patients with the high-affinity CD16 polymorphism. Blood 118, 3347–3349 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Terme, M., Ullrich, E., Delahaye, N. F., Chaput, N. & Zitvogel, L. Natural killer cell-directed therapies: moving from unexpected results to successful strategies. Nature Immunol. 9, 486–494 (2008).

    CAS  Article  Google Scholar 

  91. 91

    Thomas, E. et al. Bone marrow transplantation. N. Engl. J. Med. 292, 832–843; 895–902 (1975).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Weiden, P. L. et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N. Engl. J. Med. 300, 1068–1073 (1979).

    CAS  Article  Google Scholar 

  93. 93

    Storb, R. Allogeneic hematopoietic stem cell transplantation — yesterday, today, and tomorrow. Exp. Hematol. 31, 1–10 (2003).

    Article  PubMed  Google Scholar 

  94. 94

    Childs, R. et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N. Engl. J. Med. 343, 750–758 (2000).

    CAS  Article  PubMed  Google Scholar 

  95. 95

    Blaise, D. et al. Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors. Blood 103, 435–441 (2004).

    CAS  Article  PubMed  Google Scholar 

  96. 96

    Ferrara, J. L., Levine, J. E., Reddy, P. & Holler, E. Graft-versus-host disease. Lancet 373, 1550–1561 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Dong, Z. et al. Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells. Nature Immunol. 10, 973–980 (2009).

    CAS  Article  Google Scholar 

  98. 98

    Aversa, F. et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N. Engl. J. Med. 339, 1186–1193 (1998).

    CAS  Article  Google Scholar 

  99. 99

    Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002). A demonstration of the clinical antitumour activity of human NK cells, in the peculiar context of haplotype-mismatched, allogeneic T cell-depleted haematopoietic stem cell transplantation following administration of a myeloablative conditioning regimen.

    CAS  Article  Google Scholar 

  100. 100

    Giebel, S. et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 102, 814–819 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Ruggeri, L. et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 110, 433–440 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Kroger, N. et al. Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. Br. J. Haematol. 129, 631–643 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Bignon, J. D. & Gagne, K. KIR matching in hematopoietic stem cell transplantation. Curr. Opin. Immunol. 17, 553–559 (2005).

    CAS  Article  PubMed  Google Scholar 

  104. 104

    Poggi, A. & Zocchi, M. R. Cyclosporin A regulates human NK cell apoptosis induced by soluble HLA-I or by target cells. Autoimmun. Rev. 4, 532–536 (2005).

    CAS  Article  PubMed  Google Scholar 

  105. 105

    Wang, H. et al. The unexpected effect of cyclosporin A on CD56+CD16 and CD56+CD16+ natural killer cell subpopulations. Blood 110, 1530–1539 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Moretta, A. et al. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J. Exp. Med. 182, 875–884 (1995).

    CAS  Article  PubMed  Google Scholar 

  107. 107

    Olcese, L. et al. Killer-cell activatory receptors for MHC class I molecules are included in a multimeric complex expressed by human killer cells. J. Immunol. 158, 5083–5086 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Lanier, L. L., Corliss, B. C., Wu, J., Leong, C. & Phillips, J. H. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703–707 (1998).

    CAS  Article  Google Scholar 

  109. 109

    Verheyden, S., Schots, R., Duquet, W. & Demanet, C. A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related HLA-identical hematopoietic stem cell transplantation. Leukemia 19, 1446–1451 (2005).

    CAS  Article  PubMed  Google Scholar 

  110. 110

    De Santis, D. et al. Natural killer cell HLA-C epitopes and killer cell immunoglobulin-like receptors both influence outcome of mismatched unrelated donor bone marrow transplants. Tissue Antigens 65, 519–528 (2005).

    CAS  Article  PubMed  Google Scholar 

  111. 111

    Cook, M. et al. Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood 107, 1230–1232 (2006).

    CAS  Article  PubMed  Google Scholar 

  112. 112

    Chen, C. et al. Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders. Bone Marrow Transplant. 38, 437–444 (2006).

    CAS  Article  PubMed  Google Scholar 

  113. 113

    McQueen, K. L. et al. Donor–recipient combinations of group A and B KIR haplotypes and HLA class I ligand affect the outcome of HLA-matched, sibling donor hematopoietic cell transplantation. Hum. Immunol. 68, 309–323 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Clausen, J. et al. Impact of natural killer cell dose and donor killer-cell immunoglobulin-like receptor (KIR) genotype on outcome following human leucocyte antigen-identical haematopoietic stem cell transplantation. Clin. Exp. Immunol. 148, 520–528 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Holler, E. et al. Increased serum levels of tumor necrosis factor α precede major complications of bone marrow transplantation. Blood 75, 1011–1016 (1990).

    CAS  PubMed  Google Scholar 

  116. 116

    Storb, R. et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 89, 3048–3054 (1997).

    CAS  PubMed  Google Scholar 

  117. 117

    Giralt, S. et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 89, 4531–4536 (1997).

    CAS  PubMed  Google Scholar 

  118. 118

    Slavin, S. et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91, 756–763 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Blaise, D., Vey, N., Faucher, C. & Mohty, M. Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 92, 533–541 (2007).

    Article  PubMed  Google Scholar 

  120. 120

    Gratwohl, A. et al. The EBMT activity survey 2007 with focus on allogeneic HSCT for AML and novel cellular therapies. Bone Marrow Transplant. 43, 275–291 (2009).

    CAS  Article  PubMed  Google Scholar 

  121. 121

    Pende, D. et al. Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. Blood 113, 3119–3129 (2009).

    CAS  Article  PubMed  Google Scholar 

  122. 122

    Mohty, M. et al. Recovery of lymphocyte and dendritic cell subsets following reduced intensity allogeneic bone marrow transplantation. Hematology 7, 157–164 (2002).

    CAS  Article  PubMed  Google Scholar 

  123. 123

    Larosa, F. et al. Peripheral T-cell expansion and low infection rate after reduced-intensity conditioning and allogeneic blood stem cell transplantation. Bone Marrow Transplant. 35, 859–868 (2005).

    CAS  Article  PubMed  Google Scholar 

  124. 124

    Kim, D. H. et al. Non-CD34+ cells, especially CD8+ cytotoxic T cells and CD56+ natural killer cells, rather than CD34 cells, predict early engraftment and better transplantation outcomes in patients with hematologic malignancies after allogeneic peripheral stem cell transplantation. Biol. Blood Marrow Transplant. 12, 719–728 (2006).

    CAS  Article  PubMed  Google Scholar 

  125. 125

    Savani, B. N. et al. Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia. Leukemia 21, 2145–2152 (2007).

    CAS  Article  PubMed  Google Scholar 

  126. 126

    Dunbar, E. M. et al. The relationship between circulating natural killer cells after reduced intensity conditioning hematopoietic stem cell transplantation and relapse-free survival and graft-versus-host disease. Haematologica 93, 1852–1858 (2008).

    Article  PubMed  Google Scholar 

  127. 127

    Kolb, H. J. et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86, 2041–2050 (1995).

    CAS  PubMed  Google Scholar 

  128. 128

    Dazzi, F. et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 96, 2712–2716 (2000).

    CAS  PubMed  Google Scholar 

  129. 129

    Marks, D. I. et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 100, 3108–3114 (2002).

    CAS  Article  PubMed  Google Scholar 

  130. 130

    Shimoni, A. et al. Long-term follow-up of recipients of CD8-depleted donor lymphocyte infusions for the treatment of chronic myelogenous leukemia relapsing after allogeneic progenitor cell transplantation. Biol. Blood Marrow Transplant. 7, 568–575 (2001).

    CAS  Article  PubMed  Google Scholar 

  131. 131

    Alyea, E. P. et al. CD8+ cell depletion of donor lymphocyte infusions using CD8 monoclonal antibody-coated high-density microparticles (CD8-HDM) after allogeneic hematopoietic stem cell transplantation: a pilot study. Bone Marrow Transplant. 34, 123–128 (2004).

    CAS  Article  PubMed  Google Scholar 

  132. 132

    Porter, D. L. et al. Graft-versus-tumor induction with donor leukocyte infusions as primary therapy for patients with malignancies. J. Clin. Oncol. 17, 1234 (1999).

    CAS  Article  PubMed  Google Scholar 

  133. 133

    Guo, M. et al. Infusion of HLA-mismatched peripheral blood stem cells improves the outcome of chemotherapy for acute myeloid leukemia in elderly patients. Blood 117, 936–941 (2011).

    CAS  Article  PubMed  Google Scholar 

  134. 134

    Miller, J. S. et al. Large scale ex vivo expansion and activation of human natural killer cells for autologous therapy. Bone Marrow Transplant. 14, 555–562 (1994).

    CAS  PubMed  Google Scholar 

  135. 135

    Passweg, J. R. et al. Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia 18, 1835–1838 (2004).

    CAS  Article  Google Scholar 

  136. 136

    McKenna, D. H. Jr. et al. Good manufacturing practices production of natural killer cells for immunotherapy: a six-year single-institution experience. Transfusion 47, 520–528 (2007).

    CAS  Article  PubMed  Google Scholar 

  137. 137

    Lundqvist, A., McCoy, J. P., Samsel, L. & Childs, R. Reduction of GVHD and enhanced antitumor effects after adoptive infusion of alloreactive Ly49-mismatched NK cells from MHC-matched donors. Blood 109, 3603–3606 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Castriconi, R. et al. Human NK cell infusions prolong survival of metastatic human neuroblastoma-bearing NOD/scid mice. Cancer Immunol. Immunother. 56, 1733–1742 (2007).

    CAS  Article  PubMed  Google Scholar 

  139. 139

    Shi, J. et al. Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br. J. Haematol. 143, 641–653 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    Arai, S. et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 10, 625–632 (2008).

    CAS  Article  PubMed  Google Scholar 

  141. 141

    Cho, D. & Campana, D. Expansion and activation of natural killer cells for cancer immunotherapy. Korean J. Lab. Med. 29, 89–96 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Barkholt, L. et al. Safety analysis of ex vivo-expanded NK and NK-like T cells administered to cancer patients: a phase I clinical study. Immunotherapy 1, 753–764 (2009).

    CAS  Article  PubMed  Google Scholar 

  143. 143

    Bachanova, V. et al. Allogeneic natural killer cells for refractory lymphoma. Cancer Immunol. Immunother. 59, 1739–1744 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144

    Nguyen, S. et al. Infusion of allogeneic natural killer cells in a patient with acute myeloid leukemia in relapse after haploidentical hematopoietic stem cell transplantation. Transfusion 51, 1769–1778 (2011).

    Article  PubMed  Google Scholar 

  145. 145

    Geller, M. A. et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 13, 98–107 (2011).

    CAS  Article  PubMed  Google Scholar 

  146. 146

    De Somer, L. et al. Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells. Haematologica 96, 424–431 (2011).

    CAS  Article  PubMed  Google Scholar 

  147. 147

    Curti, A. et al. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 118, 3273–3279 (2011).

    CAS  Article  PubMed  Google Scholar 

  148. 148

    Brehm, C. et al. IL-2 stimulated but not unstimulated NK cells induce selective disappearance of peripheral blood cells: concomitant results to a phase I/II study. PLoS ONE 6, e27351 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    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). A demonstration of the safety and potential efficacy of NK cell infusion as a cancer therapy in humans.

    CAS  Article  Google Scholar 

  150. 150

    Alici, E. IPH-2101, a fully human anti-NK-cell inhibitory receptor mAb for the potential treatment of hematological cancers. Curr. Opin. Mol. Ther. 12, 724–733 (2010).

    CAS  PubMed  Google Scholar 

  151. 151

    Romagne, F. et al. Pre-clinical characterization of 1–7F9, a novel human anti-KIR therapeutic antibody that augments NK-mediated killing of tumor cells. Blood 114, 2667–2677 (2009). A characterization of the first KIR-specific human monoclonal antibody.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    Romagne, F. & Vivier, E. Natural killer cell-based therapies. F1000 Med. Rep. 3, 9 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Sola, C. et al. Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo. Proc. Natl Acad. Sci. USA 106, 12879–12884 (2009). This paper describes preclinical models of the safety and efficacy of targeting MHC class I-specific inhibitory receptors using monoclonal antibodies.

    CAS  Article  PubMed  Google Scholar 

  154. 154

    Benson, D. M. et al. A phase I study of IPH2101, a novel anti-inhibitory KIR monoclonal antibody, in patients with multiple myeloma. J. Clin. Oncol. 28 (15 suppl.), 8139 (2010).

    Article  Google Scholar 

  155. 155

    Vey, N. et al. A phase I study of the anti-natural killer inhibitory receptor (KIR) monoclonal antibody (1–7F9, IPH2101) in elderly patients with acute myeloid leukemia (AML). J. Clin. Oncol. 27 (15 suppl.), 3015 (2009).

    Google Scholar 

  156. 156

    Benson, D. M. Jr. et al. IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. Blood 118, 6387–6391 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. 157

    Walzer, T. & Vivier, E. G-protein-coupled receptors in control of natural killer cell migration. Trends Immunol. 32, 486–492 (2011).

    CAS  Article  PubMed  Google Scholar 

  158. 158

    Brand, J. M. et al. Kinetics and organ distribution of allogeneic natural killer lymphocytes transfused into patients suffering from renal cell carcinoma. Stem Cells Dev. 13, 307–314 (2004).

    CAS  Article  PubMed  Google Scholar 

  159. 159

    Sun, J. C. & Lanier, L. L. NK cell development, homeostasis and function: parallels with CD8 T cells. Nature Rev. Immunol. 11, 645–657 (2011).

    CAS  Article  Google Scholar 

  160. 160

    Park, S. H., Kyin, T., Bendelac, A. & Carnaud, C. The contribution of NKT cells, NK cells, and other γ-chain-dependent non-T non-B cells to IL-12-mediated rejection of tumors. J. Immunol. 170, 1197–1201 (2003).

    CAS  Article  PubMed  Google Scholar 

  161. 161

    Smyth, M. J. et al. Sequential production of interferon-γ by NK1.1+ T cells and natural killer cells is essential for the antimetastatic effect of α-galactosylceramide. Blood 99, 1259–1266 (2002).

    CAS  Article  PubMed  Google Scholar 

  162. 162

    Metelitsa, L. S., Weinberg, K. I., Emanuel, P. D. & Seeger, R. C. Expression of CD1d by myelomonocytic leukemias provides a target for cytotoxic NKT cells. Leukemia 17, 1068–1077 (2003).

    CAS  Article  PubMed  Google Scholar 

  163. 163

    Renukaradhya, G. J. et al. Type I NKT cells protect (and type II NKT cells suppress) the host's innate antitumor immune response to a B-cell lymphoma. Blood 111, 5637–5645 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 164

    Wu, D. Y., Segal, N. H., Sidobre, S., Kronenberg, M. & Chapman, P. B. Cross-presentation of disialoganglioside GD3 to natural killer T cells. J. Exp. Med. 198, 173–181 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Shimizu, K., Kurosawa, Y., Taniguchi, M., Steinman, R. M. & Fujii, S. Cross-presentation of glycolipid from tumor cells loaded with α-galactosylceramide leads to potent and long-lived T cell mediated immunity via dendritic cells. J. Exp. Med. 204, 2641–2653 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  166. 166

    Swann, J. B., Coquet, J. M., Smyth, M. J. & Godfrey, D. I. CD1-restricted T cells and tumor immunity. Curr. Top. Microbiol. Immunol. 314, 293–323 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Crowe, N. Y., Smyth, M. J. & Godfrey, D. I. A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J. Exp. Med. 196, 119–127 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Kammertoens, T., Qin, Z., Briesemeister, D., Bendelac, A. & Blankenstein, T. B-cells and IL-4 promote methylcholanthrene-induced carcinogenesis but there is no evidence for a role of T/NKT-cells and their effector molecules (Fas-ligand, TNF-α, perforin). Int. J. Cancer 31 Jan 2012 (doi:10.1002/ijc.27411).

    CAS  Article  PubMed  Google Scholar 

  169. 169

    Song, L. et al. Vα24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. J. Clin. Invest. 119, 1524–1536 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  170. 170

    Tahir, S. M. et al. Loss of IFN-γ production by invariant NK T cells in advanced cancer. J. Immunol. 167, 4046–4050 (2001).

    CAS  Article  Google Scholar 

  171. 171

    Yanagisawa, K. et al. Impaired proliferative response of Vα24 NKT cells from cancer patients against α-galactosylceramide. J. Immunol. 168, 6494–6499 (2002).

    CAS  Article  PubMed  Google Scholar 

  172. 172

    Tachibana, T. et al. Increased intratumor Vα24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin. Cancer Res. 11, 7322–7327 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  173. 173

    Schneiders, F. L. et al. Circulating invariant natural killer T-cell numbers predict outcome in head and neck squamous cell carcinoma: updated analysis with 10-year follow-up. J. Clin. Oncol. 30, 567–570 (2012).

    Article  PubMed  Google Scholar 

  174. 174

    Terabe, M. et al. A nonclassical non-Vα14Jα18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance. J. Exp. Med. 202, 1627–1633 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. 175

    Kawano, T. et al. Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated Vα14 NKT cells. Proc. Natl Acad. Sci. USA 95, 5690–5693 (1998).

    CAS  Article  Google Scholar 

  176. 176

    Parekh, V. V. et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Invest. 115, 2572–2583 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  177. 177

    Kim, S. et al. Impact of bacteria on the phenotype, functions, and therapeutic activities of invariant NKT cells in mice. J. Clin. Invest. 118, 2301–2315 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Cerundolo, V., Barral, P. & Batista, F. D. Synthetic iNKT cell-agonists as vaccine adjuvants — finding the balance. Curr. Opin. Immunol. 22, 417–424 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  179. 179

    Stanic, A. K. et al. Another view of T cell antigen recognition: cooperative engagement of glycolipid antigens by Va14Ja18 natural T (iNKT) cell receptor. J. Immunol. 171, 4539–4551 (2003).

    CAS  Article  Google Scholar 

  180. 180

    Oki, S., Tomi, C., Yamamura, T. & Miyake, S. Preferential Th2 polarization by OCH is supported by incompetent NKT cell induction of CD40L and following production of inflammatory cytokines by bystander cells in vivo. Int. Immunol. 17, 1619–1629 (2005).

    CAS  Article  PubMed  Google Scholar 

  181. 181

    Im, J. S. et al. Kinetics and cellular site of glycolipid loading control the outcome of natural killer T cell activation. Immunity 30, 888–898 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  182. 182

    Sullivan, B. A. et al. Mechanisms for glycolipid antigen-driven cytokine polarization by Vα14i NKT cells. J. Immunol. 184, 141–153 (2010).

    CAS  Article  Google Scholar 

  183. 183

    Yue, S. C. et al. Direct CD1d-mediated stimulation of APC IL-12 production and protective immune response to virus infection in vivo. J. Immunol. 184, 268–276 (2010).

    CAS  Article  PubMed  Google Scholar 

  184. 184

    Teng, M. W., Yue, S., Sharkey, J., Exley, M. A. & Smyth, M. J. CD1d activation and blockade: a new antitumor strategy. J. Immunol. 182, 3366–3371 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  185. 185

    Hix, L. M. et al. CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis. PLoS ONE 6, e20702 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  186. 186

    Barral, P. et al. B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo. Proc. Natl Acad. Sci. USA 105, 8345–8350 (2008).

    CAS  Article  Google Scholar 

  187. 187

    Barral, P. et al. CD169+ macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nature Immunol. 11, 303–312 (2010).

    CAS  Article  Google Scholar 

  188. 188

    Motohashi, S. et al. A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer. Clin. Cancer Res. 12, 6079–6086 (2006).

    CAS  Article  Google Scholar 

  189. 189

    Yamasaki, K. et al. Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin. Immunol. 138, 255–265 (2011).

    CAS  Article  Google Scholar 

  190. 190

    Giaccone, G. et al. A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin. Cancer Res. 8, 3702–3709 (2002).

    CAS  Google Scholar 

  191. 191

    Schneiders, F. L. et al. Clinical experience with α-galactosylceramide (KRN7000) in patients with advanced cancer and chronic hepatitis B/C infection. Clin. Immunol. 140, 130–141 (2011).

    CAS  Article  Google Scholar 

  192. 192

    Nieda, M. et al. Therapeutic activation of Vα24+Vβ11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 103, 383–389 (2004).

    CAS  Article  Google Scholar 

  193. 193

    Ishikawa, A. et al. A phase I study of α-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin. Cancer Res. 11, 1910–1917 (2005).

    CAS  Article  Google Scholar 

  194. 194

    Chang, D. H. et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J. Exp. Med. 201, 1503–1517 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  195. 195

    Kunii, N. et al. Combination therapy of in vitro-expanded natural killer T cells and α-galactosylceramide-pulsed antigen-presenting cells in patients with recurrent head and neck carcinoma. Cancer Sci. 100, 1092–1098 (2009).

    CAS  Article  Google Scholar 

  196. 196

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

    CAS  Article  Google Scholar 

  197. 197

    Paust, S. et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nature Immunol. 11, 1127–1135 (2010).

    CAS  Article  Google Scholar 

  198. 198

    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. Nature Immunol. 7, 507–516 (2006).

    CAS  Article  Google Scholar 

  199. 199

    Bukowski, J. F., Biron, C. A. & Welsh, R. M. Elevated natural killer cell-mediated cytotoxicity, plasma interferon, and tumor cell rejection in mice persistently infected with lymphocytic choriomeningitis virus. J. Immunol. 131, 991–996 (1983).

    CAS  PubMed  Google Scholar 

  200. 200

    Carnaud, C. et al. Cutting edge: cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J. Immunol. 163, 4647–4650 (1999).

    CAS  Google Scholar 

  201. 201

    Eberl, G. & MacDonald, H. R. Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells. Eur. J. Immunol. 30, 985–992 (2000).

    CAS  Article  PubMed  Google Scholar 

  202. 202

    Hermans, I. F. et al. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J. Immunol. 171, 5140–5147 (2003).

    CAS  Article  Google Scholar 

  203. 203

    Wesley, J. D. et al. Cutting edge: IFN-γ signaling to macrophages is required for optimal Vα14i NK T/NK cell cross-talk. J. Immunol. 174, 3864–3868 (2005).

    CAS  Article  PubMed  Google Scholar 

  204. 204

    Gonzalez-Aseguinolaza, G. et al. Natural killer T cell ligand α-galactosylceramide enhances protective immunity induced by malaria vaccines. J. Exp. Med. 195, 617–624 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  205. 205

    Huang, Y. et al. Enhancement of HIV DNA vaccine immunogenicity by the NKT cell ligand, α-galactosylceramide. Vaccine 26, 1807–1816 (2008).

    CAS  Article  Google Scholar 

  206. 206

    Galli, G. et al. Invariant NKT cells sustain specific B cell responses and memory. Proc. Natl Acad. Sci. USA 104, 3984–3989 (2007).

    CAS  Article  Google Scholar 

  207. 207

    Kamijuku, H. et al. Mechanism of NKT cell activation by intranasal coadministration of α-galactosylceramide, which can induce cross-protection against influenza viruses. Mucosal Immunol. 1, 208–218 (2008).

    CAS  Article  Google Scholar 

  208. 208

    Miyamoto, K., Miyake, S. & Yamamura, T. A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature 413, 531–534 (2001).

    CAS  Article  Google Scholar 

  209. 209

    Oki, S., Chiba, A., Yamamura, T. & Miyake, S. The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells. J. Clin. Invest. 113, 1631–1640 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  210. 210

    Yu, K. O. et al. Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of α-galactosylceramides. Proc. Natl Acad. Sci. USA 102, 3383–3388 (2005).

    CAS  Article  Google Scholar 

  211. 211

    Schmieg, J., Yang, G., Franck, R. W. & Tsuji, M. Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand α-galactosylceramide. J. Exp. Med. 198, 1631–1641 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  212. 212

    Chiche, L. et al. The role of natural killer cells in sepsis. J. Biomed. Biotechnol. 2011, 986491 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. 213

    Schleinitz, N., Vely, F., Harle, J. R. & Vivier, E. Natural killer cells in human autoimmune diseases. Immunology 131, 451–458 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  214. 214

    Andrews, D. M. et al. Innate immunity defines the capacity of antiviral T cells to limit persistent infection. J. Exp. Med. 207, 1333–1343 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  215. 215

    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 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. 216

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  Article  Google Scholar 

  217. 217

    Ogino, S., Galon, J., Fuchs, C. S. & Dranoff, G. Cancer immunology-analysis of host and tumor factors for personalized medicine. Nature Rev. Clin. Oncol. 8, 711–719 (2011).

    CAS  Article  Google Scholar 

  218. 218

    Benlagha, K., Weiss, A., Beavis, A., Teyton, L. & Bendelac, A. In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. J. Exp. Med. 191, 1895–1903 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  219. 219

    Matsuda, J. L. et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med. 192, 741–754 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  220. 220

    Exley, M. A. et al. Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α-chain CDR3 loop. Eur. J. Immunol. 38, 1756–1766 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  221. 221

    Pellicci, D. G. et al. Recognition of β-linked self glycolipids mediated by natural killer T cell antigen receptors. Nature Immunol. 12, 827–833 (2011). This study describes a previously unknown population of CD1d-restricted NKT cells.

    CAS  Article  Google Scholar 

  222. 222

    Brennan, P. J. et al. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nature Immunol. 12, 1202–1211 (2011). This study shows that the expression of a newly identified endogenous ligand for the NKT cell TCR is increased during some infections and promotes NKT cell activation.

    CAS  Article  Google Scholar 

  223. 223

    Brigl, M., Bry, L., Kent, S. C., Gumperz, J. E. & Brenner, M. B. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nature Immunol. 4, 1230–1237 (2003).

    CAS  Article  Google Scholar 

  224. 224

    Mattner, J. et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434, 525–529 (2005).

    CAS  Article  Google Scholar 

  225. 225

    Salio, M. et al. Modulation of human natural killer T cell ligands on TLR-mediated antigen-presenting cell activation. Proc. Natl Acad. Sci. USA 104, 20490–20495 (2007).

    CAS  Article  Google Scholar 

  226. 226

    Paget, C. et al. Activation of invariant NKT cells by Toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids. Immunity 27, 597–609 (2007).

    CAS  Article  Google Scholar 

  227. 227

    Kärre, K., Ljunggren, H. G., Piontek, G. & Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defense strategy. Nature 319, 675–678 (1986).

    Article  Google Scholar 

  228. 228

    Ljunggren, H. G. & Karre, K. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol. Today 11, 237–244 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  229. 229

    Moretta, L. et al. Allorecognition by NK cells: nonself or no self? Immunol Today 13, 300–306 (1992).

    CAS  Article  PubMed  Google Scholar 

  230. 230

    Karlhofer, F. M., Ribaudo, R. K. & Yokoyama, W. M. MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells. Nature 358, 66–70 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  231. 231

    Moretta, A. et al. Receptors for HLA class-I molecules in human natural killer cells. Annu. Rev. Immunol. 14, 619–648 (1996).

    CAS  Article  Google Scholar 

  232. 232

    Kärre, K. How to recognize a foreign submarine. Immunol. Rev. 155, 5–9 (1997).

    Article  PubMed  Google Scholar 

  233. 233

    Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  234. 234

    Vance, R. E., Kraft, J. R., Altman, J. D., Jensen, P. E. & Raulet, D. H. Mouse CD94/NKG2A is a natural killer cell receptor for the nonclassical major histocompatibility complex (MHC) class I molecule Qa-1b. J. Exp. Med. 188, 1841–1848 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  235. 235

    Vilches, C. & Parham, P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu. Rev. Immunol. 20, 217–251 (2002).

    CAS  Article  PubMed  Google Scholar 

  236. 236

    Olcese, L. et al. Human and mouse killer-cell inhibitory receptors recruit PTP1C and PTP1D protein tyrosine phosphatases. J. Immunol. 156, 4531–4534 (1996).

    CAS  PubMed  Google Scholar 

  237. 237

    Burshtyn, D. N. et al. Recruitment of tyrosine phosphatase HCP by the killer cell inhibitory receptor. Immunity 4, 77–85 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  238. 238

    Vivier, E., Nunes, J. A. & Vely, F. Natural killer cell signaling pathways. Science 306, 1517–1519 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  239. 239

    Kumar, V. & McNerney, M. E. A new self: MHC-class-I-independent natural-killer-cell self-tolerance. Nature Rev. Immunol. 5, 363–374 (2005).

    CAS  Article  Google Scholar 

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Acknowledgements

E. V. and S. U. are supported by funds from a THINK European Research Council advanced grant, the Agence Nationale de la Recherche and the Ligue Nationale Contre le Cancer, and by institutional grants from INSERM, CNRS and the Université d'Aix-Marseille to the Centre d'Immunologie de Marseille-Luminy. E.V. is a scholar of the Institut Universitaire de France, and a co-founder of and shareholder in Innate Pharma. D.B. and C.C. are supported by grants from the Institut Paoli-Calmettes, the Programme Hospitalier de Recherche Clinique (PHRC) and the Association pour la Recherche sur le Cancer. L.B. is supported by US National Institutes of Health research grants AI46709 and AI058181.

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Eric Vivier is a co-founder of and shareholder in Innate Pharma.

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Glossary

Toll-like receptors

(TLRs). A family of evolutionarily conserved pattern-recognition receptors. These molecules are located intracellularly and at the cell surface of macrophages, dendritic cells, B cells and intestinal epithelial cells. Their natural ligands are molecules that are found in bacteria, viruses and fungi.

Innate lymphoid cells

(ILCs). A group of cells of lymphoid origin that includes NK cells, LTi cells and other non-T, non-B cells that produce distinct cytokines such as IL-5, IL-13 or IL-17.

Natural killer cells

(NK cells). Non-T, non-B lymphocytes that can mediate natural killing of prototypical NK cell-sensitive targets (such as K562 cells in humans and YAC1 cells in mice) and/or produce IFNγ. In humans, NK cells typically have a NKp46+CD56+CD3 phenotype, and they are NKp46+NK1.1+CD3 in the C57BL/6 mouse strain and NKp46+CD3 in all mouse strains.

Imatinib mesylate

A first of its class tyrosine kinase inhibitor with clinical activity against chronic myeloid leukaemia associated with the t(9;22) reciprocal translocation. The introduction of imatinib mesylate into clinical practice at the end of the twentieth century induced a rapid shift in medical practices, such that allogeneic haematopoietic stem cell transplantation was abandoned as the standard treatment for this type of cancer.

CD1d

An MHC-like molecule that associates with β2-microglobulin and presents lipids.

Invariant NKT cells

(iNKT cells). A subset of T cells that possess a semi-invariant TCR. In both mice and humans, iNKT cells recognize ligands presented by CD1d.

T-bet

A member of the T-box family of transcription factors. It is a master switch in the development of T helper 1 (TH1) cells through its ability to regulate the expression of the IL-12 receptor, to inhibit signals that promote TH2 cell development and to promote the production of interferon-γ.

Perforin- and granzyme-mediated mechanisms

Granzymes are serine proteases that are found primarily in the cytoplasmic granules of cytotoxic T lymphocytes and NK cells. They enter target cells through perforin pores and then cleave and activate intracellular caspases to induce target-cell apoptosis.

CD95–CD178 pathway

CD178 (also known as FAS ligand) binds to CD95 (also known as FAS). This results in the formation of a death-inducing signalling complex and the subsequent activation of caspases, which promote the apoptosis of the CD95-expressing target cell.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A motif that is present in the cytoplasmic domains of several inhibitory receptors. After ligand binding, ITIMs are phosphorylated on their tyrosine residues and recruit lipid or tyrosine phosphatases.

DNA damage response

A cell response triggered by DNA damage, such as single or double strand breaks. The DNA damage response stops cell cycle progression to enable repair before the damage is transmitted to progeny cells. Checkpoints in the mammalian DNA damage response are controlled by the PI3K-related kinases ATM and ATR.

Immunoreceptor tyrosine-based activation motifs

(ITAMs). Activating receptors often have ITAMs consisting of a consensus amino-acid sequence with paired tyrosines and leucines (Yxx(I/L)x6–12Yxx(I/L)). These motifs are normally located in the cytoplasmic domains of ligand-binding transmembrane receptors (such as FcɛRI and the TCR), and they mediate interactions between the transmembrane receptor complex and protein tyrosine kinases, which are required to initiate early and late signalling events.

Antibody-dependent cellular cytotoxicity

(ADCC). A mechanism used by leukocytes that express Fc receptors to kill antibody-coated target cells.

Rituximab

A chimeric monoclonal antibody that is specific for the CD20 molecule, which is primarily expressed by B cells. Rituximab is the most frequently used antibody therapy for patients with cancer.

Graft-versus-leukaemia effect

The antitumour activity of donor T cells against residual leukaemic cells of the graft recipient following (allogeneic) bone marrow transplantation.

Graft-versus-host disease

(GVHD). Tissue damage in a recipient of allogeneic transplanted tissue (usually a bone marrow transplant) that results from the activity of donor cytotoxic T lymphocytes that recognize the tissue of the recipient as foreign. GVHD varies markedly in severity, but can be life threatening in severe cases. Typically, damage to the skin and gut mucosa leads to clinical manifestations.

Ciclosporin

(Also known as cyclosporin A). A commonly used immunosuppressive drug that blocks calcineurin A and thereby inhibits T cell activation. It is used to prevent the rejection of transplanted organs and to treat some inflammatory diseases. Ciclosporin is widely used to prevent graft-versus-host disease following allogeneic haematopoietic stem cell transplantation.

Reduced-intensity conditioning regimens

Regimens that use less chemotherapy and radiation than is normally used for myeloablation.

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Vivier, E., Ugolini, S., Blaise, D. et al. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 12, 239–252 (2012). https://doi.org/10.1038/nri3174

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