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Development and functions of natural killer cells

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Abstract

Over the last decade, progress in molecular and cellular biology and gene targeting techniques has removed veils from the mysteries of natural killer (NK) cell development and function. NK cells are derived from hematopoietic stem cells, for which stem cell factor or Flt3 ligand is required in the early stage of differentiation to NK cell progenitors. Interleukin 15 then plays a crucial role for differentiation and/or maturation of NK progenitors into functional NK cells. Several members of the zinc finger, ETS, and interferon regulatory factor transcription factor families are also involved in the lineage commitment of hematopoietic stem or progenitors into NK cells. Animal models as well as patients deficient in NK cells have provided formal evidence that NK cells play an important role in vivo for innate immunity against tumors and viral infections and for linkage to adaptive immunity. Moreover, recent studies have revealed novel human NK cell subsets in peripheral blood that have the phenotypical characteristics CD3-CD16+CD56+ and CD3-CD16-CD56bright, which are mainly involved in cytotoxicity and cytokine-mediated immunoregulation, respectively.

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References

  1. Herberman RB, Nunn ME, Holden HT, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors, II: characterization of effector cells.Int J Cancer. 1975;16:230–239.

    Article  CAS  PubMed  Google Scholar 

  2. Pross HF, Jondal M. Cytotoxic lymphocytes from normal donors: a functional marker of human non-T lymphocytes.Clin Exp Immunol. 1975;21:226–235.

    CAS  PubMed  Google Scholar 

  3. Trinchieri G. Biology of natural killer cells.Adv Immunol. 1989;47: 187–376.

    Article  CAS  PubMed  Google Scholar 

  4. Robertson MJ, Ritz J. Biology and clinical relevance of human natural killer cells.Blood. 1990;76:2421–2438.

    CAS  PubMed  Google Scholar 

  5. Arase H, Saito T, Phillips JH, Lanier LL. Cutting edge: the mouse NK cell-associated antigen recognized by DX5 monoclonal antibody is CD49b (alpha 2 integrin, very late antigen-2).J Immunol. 2001;167:1141–1144.

    CAS  PubMed  Google Scholar 

  6. Hackett J Jr, Bosma GC, Bosma MJ, Bennett M, Kumar V. Transplantable progenitors of natural killer cells are distinct from those of T and B lymphocytes.Proc Natl Acad Sci U S A. 1986;83: 3427–3431.

    Article  PubMed  Google Scholar 

  7. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes.Cell. 1992;68:869–877.

    Article  CAS  PubMed  Google Scholar 

  8. Shinkai Y, Rathbun G, Lam KP, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement.Cell. 1992;68:855–867.

    Article  CAS  PubMed  Google Scholar 

  9. Rodewald HR, Moingeon P, Lucich JL, Dosiou C, Lopez P, Reinherz EL. A population of early fetal thymocytes expressing Fc gamma RII/III contains precursors of T lymphocytes and natural killer cells.Cell. 1992;69:139–150.

    Article  CAS  PubMed  Google Scholar 

  10. Sanchez MJ, Muench MO, Roncarolo MG, Lanier LL, Phillips JH. Identification of a common T/natural killer cell progenitor in human fetal thymus.J Exp Med. 1994;180:569–576.

    Article  CAS  PubMed  Google Scholar 

  11. Ikawa T, Kawamoto H, Fujimoto S, Katsura Y. Commitment of common T/natural killer (NK) progenitors to unipotent T and NK progenitors in the murine fetal thymus revealed by a single progenitor assay.J Exp Med. 1999;190:1617–1626.

    Article  CAS  PubMed  Google Scholar 

  12. Michie AM, Carlyle JR, Schmitt TM, et al. Clonal characterization of a bipotent T cell and NK cell progenitor in the mouse fetal thymus.J Immunol. 2000;164:1730–1733.

    CAS  PubMed  Google Scholar 

  13. Lanier LL, Spits H, Phillips JH. The developmental relationship between NK cells and T cells.Immunol Today. 1992;13:392–395.

    Article  CAS  PubMed  Google Scholar 

  14. Spits H, Lanier LL, Phillips JH. Development of human T and natural killer cells.Blood. 1995;85:2654–2670.

    CAS  PubMed  Google Scholar 

  15. Shibuya A, Campbell D, Hannum C, et al. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes.Immunity. 1996;4:573–581.

    Article  CAS  PubMed  Google Scholar 

  16. Shibuya A, Taguchi K, Kojima H, Abe T. Inhibitory effect of granulocyte-macrophage colony-stimulating factor therapy on the generation of natural killer cells.Blood. 1991;78:3241–3247.

    CAS  PubMed  Google Scholar 

  17. Shibuya A, Kojima H, Shibuya K, Nagayoshi K, Nagasawa T, Nakauchi H. Enrichment of interleukin-2-responsive natural killer progenitors in human bone marrow.Blood. 1993;81:1819–1826.

    CAS  PubMed  Google Scholar 

  18. Miller JS,Verfaillie C, McGlave P. The generation of human natural killer cells from CD34+/DR- primitive progenitors in long-term bone marrow culture.Blood. 1992;80:2182–2187.

    CAS  PubMed  Google Scholar 

  19. Shibuya A, Nagayoshi K, Nakamura K, Nakauchi H. Lymphokine requirement for the generation of natural killer cells from CD34+ hematopoietic progenitor cells.Blood. 1995;85:3538–3546.

    CAS  PubMed  Google Scholar 

  20. Yu H, Fehniger TA, Fuchshuber P, et al. Flt3 ligand promotes the generation of a distinct CD34(+) human natural killer cell progenitor that responds to interleukin-15.Blood. 1998;92:3647–3657.

    CAS  PubMed  Google Scholar 

  21. Liu CC, Perussia B,Young JD. The emerging role of IL-15 in NKcell development.Immunol Today. 2000;21:113–116.

    Article  CAS  PubMed  Google Scholar 

  22. Grabstein KH, Eisenman J, Shanebeck K, et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor.Science. 1994;264:965–968.

    Article  CAS  PubMed  Google Scholar 

  23. Kennedy MK, Park LS. Characterization of interleukin-15 (IL-15) and the IL-15 receptor complex.J Clin Immunol. 1996;16:134–1343.

    Article  CAS  PubMed  Google Scholar 

  24. Kundig TM, Schorle H, Bachmann MF, Hengartner H, Zinkernagel RM, Horak I. Immune responses in interleukin-2-deficient mice.Science. 1993;262:1059–1061.

    Article  CAS  PubMed  Google Scholar 

  25. Suzuki H, Duncan GS, Takimoto H, Mak TW. Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain.J Exp Med. 1997;185:499–505.

    Article  CAS  PubMed  Google Scholar 

  26. Kennedy MK, Glaccum M, Brown SN, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15- deficient mice.J Exp Med. 2000;191:771–780.

    Article  CAS  PubMed  Google Scholar 

  27. Lodolce JP, Boone DL, Chai S, et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation.Immunity. 1998;9:669–676.

    Article  CAS  PubMed  Google Scholar 

  28. von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.J Exp Med. 1995;181: 1519–1526.

    Article  Google Scholar 

  29. He YW, Malek TR. Interleukin-7 receptor alpha is essential for the development of gamma delta+ T cells, but not natural killer cells.J Exp Med. 1996;184:289–293.

    Article  CAS  PubMed  Google Scholar 

  30. Magram J, Connaughton SE, Warrier RR, et al. IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses.Immunity. 1996;4:471–481.

    Article  CAS  PubMed  Google Scholar 

  31. Takeda K, Tsutsui H,Yoshimoto T, et al. Defective NK cell activity and Th1 response in IL-18-deficient mice.Immunity. 1998;8: 383–390.

    Article  CAS  PubMed  Google Scholar 

  32. Georgopoulos K, Bigby M, Wang JH, et al. The Ikaros gene is required for the development of all lymphoid lineages.Cell. 1994; 79:143–156.

    Article  CAS  PubMed  Google Scholar 

  33. Norton JD, Deed RW, Craggs G, Sablitzky F. Id helix-loop-helix proteins in cell growth and differentiation.Trends Cell Biol. 1998; 8:58–65.

    Article  CAS  PubMed  Google Scholar 

  34. Yokota Y, Mansouri A, Mori S, et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loophelix inhibitor Id2.Nature. 1999;397:702–706.

    Article  CAS  PubMed  Google Scholar 

  35. Sharrocks AD, Brown AL, Ling Y, Yates PR. The ETS-domain transcription factor family.Int J Biochem Cell Biol. 1997;29: 1371–1387.

    Article  CAS  PubMed  Google Scholar 

  36. Barton K, Muthusamy N, Fischer C, et al. The Ets-1 transcription factor is required for the development of natural killer cells in mice.Immunity. 1998;9:555–563.

    Article  CAS  PubMed  Google Scholar 

  37. Lacorazza HD, Miyazaki Y, Di Cristofano A, et al.The ETS protein MEF plays a critical role in perforin gene expression and the development of natural killer and NK-T cells.Immunity. 2002;17: 437–449.

    Article  CAS  PubMed  Google Scholar 

  38. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. IRF family of transcription factors as regulators of host defense.Annu Rev Immunol. 2001;19:623–655.

    Article  CAS  PubMed  Google Scholar 

  39. Miyamoto M, Fujita T, Kimura Y, et al. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements.Cell. 1988;54:903–913.

    Article  CAS  PubMed  Google Scholar 

  40. Harada H, Fujita T, Miyamoto M, et al. Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes.Cell. 1989;58: 729–739.

    Article  CAS  PubMed  Google Scholar 

  41. Duncan GS, Mittrucker HW, Kagi D, Matsuyama T, Mak TW. The transcription factor interferon regulatory factor-1 is essential for natural killer cell function in vivo.J Exp Med. 1996;184:2043–2048.

    Article  CAS  PubMed  Google Scholar 

  42. Taki S, Sato T, Ogasawara K, et al. Multistage regulation of Th1- type immune responses by the transcription factor IRF-1.Immunity. 1997;6:673–679.

    Article  CAS  PubMed  Google Scholar 

  43. Ohteki T,Yoshida H, Matsuyama T, Duncan GS,Mak TW, Ohashi PS. The transcription factor interferon regulatory factor 1 (IRF-1) is important during the maturation of natural killer 1.1+ T cell receptoralpha/ beta+ (NK1+ T) cells, natural killer cells, and intestinal intraepithelial T cells.J Exp Med. 1998;187:967–972.

    Article  CAS  PubMed  Google Scholar 

  44. Ogasawara K, Hida S,Azimi N, et al. Requirement for IRF-1 in the microenvironment supporting development of natural killer cells.Nature. 1998;391:700–703.

    Article  CAS  PubMed  Google Scholar 

  45. Lohoff M, Duncan GS, Ferrick D, et al. Deficiency in the transcription factor interferon regulatory factor (IRF)-2 leads to severely compromised development of natural killer and T helper type 1 cells.J Exp Med. 2000;192:325–336.

    Article  CAS  PubMed  Google Scholar 

  46. Biron CA, Byron KS, Sullivan JL. Severe herpesvirus infections in an adolescent without natural killer cells.N Engl J Med. 1989;320: 1731–1735.

    Article  CAS  PubMed  Google Scholar 

  47. Ballas ZK, Turner JM, Turner DA, Goetzman EA, Kemp JD. A patient with simultaneous absence of “classical” natural killer cells (CD3-, CD16+, and NKH1+) and expansion of CD3+, CD4-, CD8-, NKH1+ subset.J Allergy Clin Immunol. 1990;85:453–459.

    Article  CAS  PubMed  Google Scholar 

  48. Joncas J, Monczak Y, Ghibu F, et al. Brief report: killer cell defect and persistent immunological abnormalities in two patients with chronic active Epstein-Barr virus infection.J Med Virol. 1989;28: 110–117.

    Article  CAS  PubMed  Google Scholar 

  49. Bukowski JF,Warner JF, Dennert G,Welsh RM. Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo.J Exp Med. 1985;161:40–52.

    Article  PubMed  Google Scholar 

  50. Welsh RM, Brubaker JO,Vargas-Cortes M, O’Donnell CL. Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency: the stimulation of NK cells and the NK cell-dependent control of virus infections occur independently of T and B cell function.J Exp Med. 1991;173:1053–1063.

    Article  CAS  PubMed  Google Scholar 

  51. Scalzo AA, Fitzgerald NA, Simmons A, La Vista AB, Shellam GR. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen.J Exp Med. 1990;171:1469–1483.

    Article  CAS  PubMed  Google Scholar 

  52. Scalzo AA, Fitzgerald NA, Wallace CR, et al. The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells.J Immunol. 1992; 149:581–589.

    CAS  PubMed  Google Scholar 

  53. Forbes CA, Brown MG, Cho R, Shellam GR, Yokoyama WM, Scalzo AA.The Cmv1 host resistance locus is closely linked to the Ly49 multigene family within the natural killer cell gene complex on mouse chromosome 6.Genomics. 1997;41:406–413.

    Article  CAS  PubMed  Google Scholar 

  54. Brown MG, Dokun AO, Heusel JW, et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection.Science. 2001;292:934–937.

    Article  CAS  PubMed  Google Scholar 

  55. Daniels KA, Devora G, Lai WC, O’Donnell CL, Bennett M, Welsh RM. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H.J Exp Med. 2001;194:29–44.

    Article  CAS  PubMed  Google Scholar 

  56. Lee SH, Girard S, Macina D, 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. 2001;28:42–45.

    Article  CAS  PubMed  Google Scholar 

  57. Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors.Science. 2002;296:1323–1326.

    Article  CAS  PubMed  Google Scholar 

  58. Lanier LL, Corliss BC, Wu J, Leong C, Phillips JH. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.Nature. 1998;391:703–707.

    Article  CAS  PubMed  Google Scholar 

  59. Smith KM,Wu J, Bakker AB, Phillips JH, Lanier LL. Ly-49D and Ly-49H associate with mouse DAP12 and form activating receptors.J Immunol. 1998;161:7–10.

    CAS  PubMed  Google Scholar 

  60. Kim S, Iizuka K, Aguila HL,Weissman IL,Yokoyama WM. In vivo natural killer cell activities revealed by natural killer cell-deficient mice.Proc Natl Acad Sci U S A. 2000;97:2731–2736.

    Article  CAS  PubMed  Google Scholar 

  61. Lanier LL, Le AM, Civin CI, Loken MR, Phillips JH. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes.J Immunol. 1986;136:4480–4486.

    CAS  PubMed  Google Scholar 

  62. Nagler A, Lanier LL, Cwirla S, Phillips JH. Comparative studies of human FcRIII-positive and negative natural killer cells.J Immunol. 1989;143:3183–3191.

    CAS  PubMed  Google Scholar 

  63. Nagler A, Lanier LL, Phillips JH. Constitutive expression of high affinity interleukin 2 receptors on human CD16-natural killer cells in vivo.J Exp Med. 1990;171:1527–1533.

    Article  CAS  PubMed  Google Scholar 

  64. Robertson MJ, Soiffer RJ, Wolf SF, et al. Response of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): cytolytic activity and proliferation of NK cells are differentially regulated by NKSF.J Exp Med. 1992;175:779–788.

    Article  CAS  PubMed  Google Scholar 

  65. Lanier LL. Turning on natural killer cells.J Exp Med. 2000;191: 1259–1262.

    Article  CAS  PubMed  Google Scholar 

  66. Lanier LL. On guard-activating NK cell receptors.Nat Immunol. 2001;2:23–27.

    Article  CAS  PubMed  Google Scholar 

  67. Lanier LL. NK cell receptors.Annu Rev Immunol. 1998;16:359–393.

    Article  CAS  PubMed  Google Scholar 

  68. Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer.Nat Rev Immunol. 2001;1:41–49.

    Article  CAS  PubMed  Google Scholar 

  69. Andre P, Spertini O, Guia S, et al. Modification of P-selectin glycoprotein ligand-1 with a natural killer cell-restricted sulfated lactosamine creates an alternate ligand for L-selectin.Proc Natl Acad Sci U S A. 2000;97:3400–3405.

    Article  CAS  PubMed  Google Scholar 

  70. Voss SD, Daley J, Ritz J, Robertson MJ. Participation of the CD94 receptor complex in costimulation of human natural killer cells.J Immunol. 1998;160:1618–1626.

    CAS  PubMed  Google Scholar 

  71. Unanue ER. Inter-relationship among macrophages, natural killer cells and neutrophils in early stages of Listeria resistance.Curr Opin Immunol. 1997;9:35–43.

    Article  CAS  PubMed  Google Scholar 

  72. Doolan DL, Hoffman SL. IL-12 and NK cells are required for antigen-specific adaptive immunity against malaria initiated by CD8+ T cells in the Plasmodium yoelii model.J Immunol. 1999; 163:884–892.

    CAS  PubMed  Google Scholar 

  73. Denkers EY, Gazzinelli RT, MartinD, Sher A. Emergence of NK1.1+ cells as effectors of IFN-gamma dependent immunity to Toxoplasma gondii inMHCclass I-deficient mice.J Exp Med. 1993;178:1465–1472.

    Article  CAS  PubMed  Google Scholar 

  74. Sher A, Oswald IP, Hieny S, Gazzinelli RT. Toxoplasma gondii induces a T-independent IFN-gamma response in natural killer cells that requires both adherent accessory cells and tumor necrosis factor-alpha.J Immunol. 1993;150:3982–3989.

    CAS  PubMed  Google Scholar 

  75. Cooper MA, Fehniger TA, Turner SC, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset.Blood. 2001;97:3146–3151.

    Article  CAS  PubMed  Google Scholar 

  76. Cooper MA, Fehniger TA, Ponnappan A, Mehta V, Wewers MD, Caligiuri MA. Interleukin-1beta costimulates interferon-gamma production by human natural killer cells.Eur J Immunol. 2001;31: 792–801.

    Article  CAS  PubMed  Google Scholar 

  77. Kunikata T, Torigoe K, Ushio S, et al. Constitutive and induced IL-18 receptor expression by various peripheral blood cell subsets as determined by anti-hIL-18R monoclonal antibody.Cell Immunol. 1998;189:135–143.

    Article  CAS  PubMed  Google Scholar 

  78. Caligiuri MA, Zmuidzinas A, Manley TJ, Levine H, Smith KA, Ritz J. Functional consequences of interleukin 2 receptor expression on resting human lymphocytes: identification of a novel natural killer cell subset with high affinity receptors.J Exp Med. 1990; 171:1509–1526.

    Article  CAS  PubMed  Google Scholar 

  79. Voss SD, Sondel PM, Robb RJ. Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2R gamma chain with the IL-2R beta chain in functional intermediate-affinity IL-2R.J Exp Med. 1992;176:531–541.

    Article  CAS  PubMed  Google Scholar 

  80. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets.Trends Immunol. 2001;22:633–640.

    Article  CAS  PubMed  Google Scholar 

  81. Raulet DH. Development and tolerance of natural killer cells.Curr Opin Immunol. 1999;11:129–134

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Immunology, Institute of Basic Medical Sciences, University of Tsukuba, 305-8575, Tsukuba, Ibaraki, Japan

    Akira Shibuya

  2. PRESTO, Japan Science and Technology Corporation, Ibaraki

    Akira Shibuya

  3. Laboratory for Immune Receptor, RIKEN Research Center for Allergy and Immunology, Ibaraki, Japan

    Akira Shibuya

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Correspondence to Akira Shibuya.

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Shibuya, A. Development and functions of natural killer cells. Int J Hematol 78, 1–6 (2003). https://doi.org/10.1007/BF02983233

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