Review Article | Published:

Functions of natural killer cells

Nature Immunology volume 9, pages 503510 (2008) | Download Citation

Subjects

Abstract

Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Recent research highlights the fact that NK cells are also regulatory cells engaged in reciprocal interactions with dendritic cells, macrophages, T cells and endothelial cells. NK cells can thus limit or exacerbate immune responses. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Biology of natural killer cells. Adv. Immunol. 47, 187–376 (1989).

  2. 2.

    , & Natural killer cell signaling pathways. Science 306, 1517–1519 (2004).

  3. 3.

    NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005).

  4. 4.

    et al. CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells. Proc. Natl. Acad. Sci. USA 101, 10116–10121 (2004).

  5. 5.

    et al. The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J. Immunol. 174, 727–734 (2005).

  6. 6.

    , , & TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-γ production. J. Immunol. 175, 1636–1642 (2005).

  7. 7.

    & Immune functions encoded by the natural killer gene complex. Nat. Rev. Immunol. 3, 304–316 (2003).

  8. 8.

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

  9. 9.

    , , & Selective rejection of H-2–deficient lymphoma variants suggests alternative immune defense strategy. Nature 319, 675–678 (1986).

  10. 10.

    & A new self: MHC-class-I-independent natural-killer-cell self-tolerance. Nat. Rev. Immunol. 5, 363–374 (2005).

  11. 11.

    et al. The trafficking of natural killer cells. Immunol. Rev. 220, 169–182 (2007).

  12. 12.

    et al. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 121, 258–265 (2007).

  13. 13.

    , , , & Turnover and proliferation of NK cells in steady state and lymphopenic conditions. J. Immunol. 172, 864–870 (2004).

  14. 14.

    et al. Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proc. Natl. Acad. Sci. USA 104, 3384–3389 (2007).

  15. 15.

    & CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J. Immunol. 176, 1517–1524 (2006).

  16. 16.

    et al. In vivo developmental stages in murine natural killer cell maturation. Nat. Immunol. 3, 523–528 (2002).

  17. 17.

    , & The biology of human natural killer-cell subsets. Trends Immunol. 22, 633–640 (2001).

  18. 18.

    et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity 25, 331–342 (2006).

  19. 19.

    & NK cell compartments and their activation by dendritic cells. J. Immunol. 172, 1333–1339 (2004).

  20. 20.

    & Human natural killer cell development. Immunol. Rev. 214, 56–72 (2006).

  21. 21.

    , , , & Suppression of tumor formation in lymph nodes by L-selectin-mediated natural killer cell recruitment. J. Exp. Med. 202, 1679–1689 (2005).

  22. 22.

    et al. Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat. Immunol. 8, 1337–1344 (2007).

  23. 23.

    et al. CCR7 ligands, SLC/6Ckine/Exodus2/TCA4 and CKβ-11/MIP-3β/ELC, are chemoattractants for CD56+CD16 NK cells and late stage lymphoid progenitors. Cell. Immunol. 193, 226–235 (1999).

  24. 24.

    et al. The role of chemerin in the colocalization of NK and dendritic cell subsets into inflamed tissues. Blood 109, 3625–3632 (2007).

  25. 25.

    Ready for prime time: NK cell priming by dendritic cells. Immunity 26, 385–387 (2007).

  26. 26.

    , , , & Natural-killer cells and dendritic cells: “l'union fait la force.” Blood 106, 2252–2258 (2005).

  27. 27.

    et al. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 101, 3052–3057 (2003).

  28. 28.

    et al. CD8 T cell help for innate antitumor immunity. J. Immunol. 179, 6651–6662 (2007).

  29. 29.

    , , & Transforming growth factor-β controls T helper type 1 cell development through regulation of natural killer cell interferon-γ. Nat. Immunol. 6, 600–607 (2005).

  30. 30.

    et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner. J. Exp. Med. 202, 1075–1085 (2005).

  31. 31.

    et al. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J. Immunol. 176, 1582–1587 (2006).

  32. 32.

    et al. Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 26, 798–811 (2007).

  33. 33.

    , , & Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107, 159–166 (2006).

  34. 34.

    , , , & Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26, 503–517 (2007).

  35. 35.

    , , , & Natural killer cell tolerance in mice with mosaic expression of major histocompatibility complex class I transgene. J. Exp. Med. 186, 353–364 (1997).

  36. 36.

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

  37. 37.

    et al. Hierarchy of the human natural killer cell response is determined by class and quantity of inhibitory receptors for self-HLA-B and HLA-C ligands. J. Immunol. 179, 5977–5989 (2007).

  38. 38.

    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).

  39. 39.

    & Self-tolerance of natural killer cells. Nat. Rev. Immunol. 6, 520–531 (2006).

  40. 40.

    & Strategies of NK cell recognition and their roles in tumor immunosurveillance. in How the Immune System Recognizes Self and Nonself: Immunoreceptors and Their Signaling (ed. Kitamura, D.) 37–81 (Springer, Tokyo, 2007).

  41. 41.

    , , & Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165–171 (2001).

  42. 42.

    , & Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc. Natl. Acad. Sci. USA 98, 11521–11526 (2001).

  43. 43.

    et al. Induction of tumor-specific T cell memory by NK cell–mediated tumor rejection. Nat. Immunol. 3, 83–90 (2002).

  44. 44.

    et al. NKG2D function protects the host from tumor initiation. J. Exp. Med. 202, 583–588 (2005).

  45. 45.

    et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and γδ T cells. J. Exp. Med. 199, 879–884 (2004).

  46. 46.

    Human natural killer cell deficiencies. Curr. Opin. Allergy Clin. Immunol. 6, 399–409 (2006).

  47. 47.

    , , , & 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).

  48. 48.

    , , & Allogeneic hematopoietic transplantation and natural killer cell recognition of missing self. Immunol. Rev. 214, 202–218 (2006).

  49. 49.

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

  50. 50.

    et al. Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo. Blood 97, 3132–3137 (2001).

  51. 51.

    & Prospects for the use of NK cells in immunotherapy of human cancer. Nat. Rev. Immunol. 7, 329–339 (2007).

  52. 52.

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

  53. 53.

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

  54. 54.

    , & Keeping NK cells in highly regulated antiviral warfare. Trends Immunol. 28, 252–259 (2007).

  55. 55.

    , , , & The interplay between host and viral factors in shaping the outcome of cytomegalovirus infection. Immunol. Cell Biol. 85, 46–54 (2007).

  56. 56.

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

  57. 57.

    , , , & Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002).

  58. 58.

    et al. Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell–mediated innate resistance to cytomegalovirus infection. Nat. Genet. 37, 593–599 (2005).

  59. 59.

    et al. Interferon α/β and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J. Exp. Med. 195, 517–528 (2002).

  60. 60.

    , , , & Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).

  61. 61.

    & NK cell recognition of mouse cytomegalovirus-infected cells. Curr. Top. Microbiol. Immunol. 298, 183–206 (2006).

  62. 62.

    et al. Cytomegalovirus evasion of innate immunity by subversion of the NKR-P1:Ocil/Clr-b missing-self axis. Immunity 26, 617–627 (2007).

  63. 63.

    Human primary immunodeficiency diseases. Immunity 27, 835–845 (2007).

  64. 64.

    Interplay of natural killer cells and their receptors with the adaptive immune response. Nat. Immunol. 5, 996–1002 (2004).

  65. 65.

    , , & Role of natural killer cells as immune effectors in encephalitis and demyelination induced by Theiler's virus. J. Immunol. 143, 95–102 (1989).

  66. 66.

    , , , & From infection to autoimmunity. J. Autoimmun. 16, 175–186 (2001).

  67. 67.

    et al. Natural killer cells promote early CD8 T cell responses against cytomegalovirus. PLoS Pathog. 3, e123 (2007).

  68. 68.

    et al. Perforin and granzymes have distinct roles in defensive immunity and immunopathology. Immunity 25, 835–848 (2006).

  69. 69.

    Hemophagocytic syndromes. Blood Rev. 21, 245–253 (2007).

  70. 70.

    , , & An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 104, 735–743 (2004).

  71. 71.

    et al. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J. Exp. Med. 204, 853–863 (2007).

  72. 72.

    et al. Reciprocal regulation of natural killer cells and macrophages associated with distinct immune synapses. Blood 109, 3776–3785 (2007).

  73. 73.

    et al. Effector and regulatory events during natural killer-dendritic cell interactions. Immunol. Rev. 214, 219–228 (2006).

  74. 74.

    & Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat. Rev. Immunol. 5, 112–124 (2005).

  75. 75.

    , , & Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J. Exp. Med. 195, 335–341 (2002).

  76. 76.

    et al. NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. J. Immunol. 172, 123–129 (2004).

  77. 77.

    , , , & NK cells promote transplant tolerance by killing donor antigen-presenting cells. J. Exp. Med. 203, 1851–1858 (2006).

  78. 78.

    et al. Inflammatory arthritis can be reined in by CpG-induced DC NK cell cross talk. J. Exp. Med. 204, 1911–1922 (2007).

  79. 79.

    et al. Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nat. Immunol. 5, 1260–1265 (2004).

  80. 80.

    , , , & NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-γ secretion. Eur. J. Immunol. 36, 2394–2400 (2006).

  81. 81.

    et al. Regulation of activated CD4+ T cells by NK cells via the Qa-1–NKG2A inhibitory pathway. Immunity 26, 593–604 (2007).

  82. 82.

    & The development of autoimmunity in C57BL/6 lpr mice correlates with the disappearance of natural killer type 1-positive cells: evidence for their suppressive action on bone marrow stem cell proliferation, B cell immunoglobulin secretion, and autoimmune symptoms. J. Exp. Med. 177, 155–164 (1993).

  83. 83.

    , , & NK cells: elusive players in autoimmunity. Trends Immunol. 26, 613–618 (2005).

  84. 84.

    et al. Fractalkine-mediated endothelial cell injury by NK cells. J. Immunol. 164, 4055–4062 (2000).

  85. 85.

    & Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction. Blood 111, 175–182 (2008).

  86. 86.

    & Xenograft rejection: IgG1, complement and NK cells team up to activate and destroy the endothelium. Trends Immunol. 26, 2–5 (2005).

  87. 87.

    , , & Uterine natural killer cells: a specialized differentiation regulated by ovarian hormones. Immunol. Rev. 214, 161–185 (2006).

  88. 88.

    et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat. Med. 12, 1065–1074 (2006).

  89. 89.

    & How does the maternal immune system contribute to the development of pre-eclampsia? Placenta 28 (suppl. A), S51–S56 (2007).

  90. 90.

    et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J. Exp. Med. 204, 667–680 (2007).

  91. 91.

    et al. Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology 46, 706–715 (2007).

  92. 92.

    et al. Identification of a detrimental role for NK cells in pneumococcal pneumonia and sepsis in immunocompromised hosts. Microbes Infect. 7, 845–852 (2005).

  93. 93.

    et al. Natural killer cells contribute to the lethality of a murine model of Escherichia coli infection. Surgery 132, 205–212 (2002).

  94. 94.

    et al. Target cell defense prevents the development of diabetes after viral infection. Nat. Immunol. 3, 373–382 (2002).

  95. 95.

    , & Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Proc. Natl. Acad. Sci. USA 101, 8102–8107 (2004).

  96. 96.

    et al. Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion. Immunology 122, 291–301 (2007).

  97. 97.

    , , , & Characterisation of natural killer cells and CD56+ T-cells in sarcoidosis patients. Eur. Respir. J. 26, 77–85 (2005).

  98. 98.

    , , & T cell– and B cell–independent adaptive immunity mediated by natural killer cells. Nat. Immunol. 7, 507–516 (2006).

  99. 99.

    et al. Natural killer cells in vernal keratoconjunctivitis. Mol. Vis. 13, 1562–1567 (2007).

  100. 100.

    et al. Natural killer and dendritic cell contact in lesional atopic dermatitis skin – Malassezia-influenced cell interaction. J. Invest. Dermatol. 119, 850–857 (2002).

  101. 101.

    et al. CD56brightCD16 NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation. Eur. J. Immunol. 36, 118–128 (2006).

  102. 102.

    , , & Characteristics of natural killer cells in the murine intestinal epithelium and lamina propria. J. Exp. Med. 155, 1785–1796 (1982).

  103. 103.

    , & Natural killer cells and innate immunity to protozoan pathogens. Int. J. Parasitol. 34, 1517–1528 (2004).

  104. 104.

    et al. Natural killer cells and malaria. Immunol. Rev. 214, 251–263 (2006).

  105. 105.

    et al. Characterization of CD56/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc. Natl. Acad. Sci. USA 102, 2886–2891 (2005).

  106. 106.

    et al. Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J. Exp. Med. 204, 3027–3036 (2007).

  107. 107.

    et al. Cutting edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation. J. Immunol. 178, 647–651 (2007).

  108. 108.

    , & NK cytotoxicity against CD4+ T cells during HIV-1 infection: a gp41 peptide induces the expression of an NKp44 ligand. Proc. Natl. Acad. Sci. USA 102, 10981–10986 (2005).

  109. 109.

    , , , & In vivo natural killer cell activities revealed by natural killer cell- deficient mice. Proc. Natl. Acad. Sci. USA 97, 2731–2736 (2000).

Download references

Acknowledgements

We thank all the past and present members of the E.V. lab, and in particular S. Guia and C. Cognet. We also thank K. Hoebe for communication of unpublished results and C. Beziers-Lafosse for help with the illustrations. Because of space limitations, certain studies could not be quoted, and we apologize to colleagues for such omissions. Supported by INSERM, Centre National de la Recherche Scientifique, the European Union ('ALLOSTEM'), Ligue Nationale contre le Cancer ('Equipe labellisée La Ligue'), the Agence Nationale de la Recherche ('Réseau Innovation Biotechnologies'; 'Microbiologie Immunologie – Maladies Emergentes'; 'Maladies Rares'; 'Plates-Formes Technologiques du Vivant'), Institut National du Cancer, Ministère de l'Enseignement Supérieur et de la Recherche and Institut Universitaire de France.

Author information

Affiliations

  1. Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, case 906, Campus de Luminy, 13288 Marseille, France.

    • Eric Vivier
    • , Elena Tomasello
    • , Myriam Baratin
    • , Thierry Walzer
    •  & Sophie Ugolini
  2. INSERM, U631, case 906, Campus de Luminy, 13288 Marseille, France.

    • Eric Vivier
    • , Elena Tomasello
    • , Myriam Baratin
    • , Thierry Walzer
    •  & Sophie Ugolini
  3. Centre National de la Recherche Scientifique, UMR6102, case 906, Campus de Luminy, 13288 Marseille, France.

    • Eric Vivier
    • , Elena Tomasello
    • , Myriam Baratin
    • , Thierry Walzer
    •  & Sophie Ugolini
  4. Hôpital de la Conception, Assistance Publique – Hôpitaux de Marseille, 147 boulevard Baille 13385 Marseille France.

    • Eric Vivier

Authors

  1. Search for Eric Vivier in:

  2. Search for Elena Tomasello in:

  3. Search for Myriam Baratin in:

  4. Search for Thierry Walzer in:

  5. Search for Sophie Ugolini in:

Competing interests

E.V. is a founder, consultant and shareholder of Innate-Pharma.

Corresponding author

Correspondence to Eric Vivier.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Table 1

About this article

Publication history

Published

DOI

https://doi.org/10.1038/ni1582

Further reading