Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Immune functions encoded by the natural killer gene complex

Key Points

  • The natural killer gene complex (NKC) encodes type II lectin-like molecules, many of which are involved in natural killer (NK)-cell recognition.

  • Genes spanning the NKC are organized into clusters that encode highly related molecules, mostly inhibitory or activating receptors characterized by the presence of cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or positively-charged transmembrane residues, respectively.

  • ;So far, ligands for NKC-encoded NK-cell receptors belong to the MHC class I superfamily.

  • The NKC-encoded receptors have ligand-binding affinities comparable to other immune receptors involved in cell–cell interactions, with the exception of NKG2D, which can bind with higher affinity.

  • Available crystal structures show similarities to the classical C-type lectin fold (absent Ca2+-binding residues) and at least two ligand-binding strategies.

  • NKC-encoded receptors participate in tumour and viral immunity.

  • The NKC displays marked polymorphism and is genetically linked to immune phenotypes that include resistance to viral infections and target specificity.

  • Rodent Ly49 receptors and human KIR receptors are structurally divergent yet functionally analogous receptors, supporting the concept of co-evolutionary development with the MHC.

  • An NKC-related receptor has been discovered in tunicates, indicating that the NKC antedates the development of adaptive immunity.

  • Emerging data support the broader role of other NKC receptors in innate immune responses.

Abstract

There has been marked progress in our understanding of the role of natural killer (NK) cells in immune responses, mainly due to the identification of NK-cell receptors and their ligands. The genes encoding many NK-cell receptors are located in the NK-gene complex (NKC). Here, we review the properties of NKC-encoded receptors, and provide a genomic and conceptual framework for an insight into NK-cell function and biology.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: NK cells express three types of receptors: activating, inhibitory and co-stimulatory receptors.
Figure 2: Lectin-like molecules encoded in the natural killer gene complex.
Figure 3: Genomic structure of lectin-like receptors encoded in the natural killer gene complex.
Figure 4: A new tumour-evasion strategy.

Similar content being viewed by others

References

  1. Yokoyama, W. M. in Fundamental Immunology (ed. Paul, W. E.) 575–603 (Lippincott–Raven, New York, 1999).

    Google Scholar 

  2. Kärre, K., Ljunggren, H. G., Piontek, G. & Kiessling, R. Selective rejection of H–2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675–678 (1986). This paper describes studies that led to the 'missing-self' hypothesis.

    PubMed  Google Scholar 

  3. Long, E. O. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 17, 875–904 (1999).

    CAS  PubMed  Google Scholar 

  4. Moretta, L., Biassoni, R., Bottino, C., Mingari, M. C. & Moretta, A. Human NK-cell receptors. Immunol. Today 21, 420–422 (2000).

    CAS  PubMed  Google Scholar 

  5. Colonna, M., Nakajima, H. & Cella, M. A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. Semin. Immunol. 12, 121–127 (2000).

    CAS  PubMed  Google Scholar 

  6. Yokoyama, W. M. & Seaman, W. E. The Ly49 and NKRP1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex. Annu. Rev. Immunol. 11, 613–635 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Lopez-Botet, M., Llano, M., Navarro, F. & Bellon, T. NK cell recognition of non-classical HLA class I molecules. Semin. Immunol. 12, 109–119 (2000).

    CAS  PubMed  Google Scholar 

  8. Wang, J. W. et al. Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation. Science 295, 2094–2097 (2002).

    CAS  PubMed  Google Scholar 

  9. Tomasello, E. et al. Gene structure, expression pattern, and biological activity of mouse killer cell activating receptor-associated protein (KARAP)/DAP-12. J. Biol. Chem. 273, 34115–34119 (1998).

    CAS  PubMed  Google Scholar 

  10. Smith, K. M., Wu, J., Bakker, A. B., Phillips, J. H. & Lanier, L. L. Cutting edge: Ly49D and Ly49H associate with mouse DAP12 and form activating receptors. J. Immunol. 161, 7–10 (1998).

    CAS  PubMed  Google Scholar 

  11. Lanier, L. L., Cortiss, 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  PubMed  Google Scholar 

  12. Arase, N. et al. Association with FcR-γ is essential for activation signal through NKRP1 (CD161) in natural killer (NK) cells and NK1.1+ T cells. J. Exp. Med. 186, 1957–1963 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wende, H., Volz, A. & Ziegler, A. Extensive gene duplications and a large inversion characterize the human leukocyte receptor cluster. Immunogenetics 51, 703–713 (2000).

    CAS  PubMed  Google Scholar 

  14. Chambers, W. H. et al. Monoclonal antibody to a triggering structure expressed on rat natural killer cells and adherent lymphokine-activated killer cells. J. Exp. Med. 169, 1373–1389 (1989).

    CAS  PubMed  Google Scholar 

  15. Karlhofer, F. M., Ribaudo, R. K. & Yokoyama, W. M. MHC class I alloantigen specificity of Ly49+ IL-2-activated natural killer cells. Nature 358, 66–70 (1992). This was the first description of an MHC class-I-specific inhibitory receptor (Ly49a) on natural killer (NK) cells.

    CAS  PubMed  Google Scholar 

  16. Yokoyama, W. M., Kehn, P. J., Cohen, D. I. & Shevach, E. M. Chromosomal location of the Ly49 (A1, YE1/48) multigene family. Genetic association with the NK1.1 antigen. J. Immunol. 145, 2353–2358 (1990).

    CAS  PubMed  Google Scholar 

  17. Yokoyama, W. M. et al. cDNA cloning of mouse NKRP1 and genetic linkage with Ly49. Identification of a natural killer cell gene complex on mouse chromosome 6. J. Immunol. 147, 3229–3236 (1991). The initial description of the NK gene complex (NKC).

    CAS  PubMed  Google Scholar 

  18. Chan, P. Y. & Takei, F. Molecular cloning and characterization of a novel murine T cell surface antigen, YE1/48. J. Immunol. 142, 1727–1736 (1989).

    CAS  PubMed  Google Scholar 

  19. Yokoyama, W. M., Jacobs, L. B., Kanagawa, O., Shevach, E. M. & Cohen, D. I. A murine T lymphocyte antigen belongs to a supergene family of type II integral membrane proteins. J. Immunol. 143, 1379–1386 (1989).

    CAS  PubMed  Google Scholar 

  20. Giorda, R. et al. NKRP1, a signal transduction molecule on natural killer cells. Science 249, 1298–1300 (1990).

    CAS  PubMed  Google Scholar 

  21. Houchins, J. P., Yabe, T., McSherry, C. & Bach, F. H. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J. Exp. Med. 173, 1017–1020 (1991).

    CAS  PubMed  Google Scholar 

  22. Renedo, M. et al. The human natural killer gene complex is located on chromosome 12p12–p13. Immunogenetics 46, 307–311 (1997).

    CAS  PubMed  Google Scholar 

  23. Wilhelm, B. T., Gagnier, L. & Mager, D. L. Sequence analysis of the Ly49 cluster in C57BL/6 mice: a rapidly evolving multigene family in the immune system. Genomics 80, 646–661 (2002).

    CAS  PubMed  Google Scholar 

  24. Silver, E. T., Elliott, J. F. & Kane, K. P. Alternatively spliced LY49D and H transcripts are found in IL-2-activated NK cells. Immunol. Today 44, 14–17 (1996).

    Google Scholar 

  25. Brown, M. G. et al. A 2-Mb YAC contig and physical map of the natural killer gene complex on mouse chromosome 6. Genomics 42, 16–25 (1997).

    CAS  PubMed  Google Scholar 

  26. Makrigiannis, A. P. et al. A BAC contig map of the Ly49 gene cluster in 129 mice reveals extensive differences in gene content relative to C57BL/6 mice. Genomics 79, 437–444 (2002).

    CAS  PubMed  Google Scholar 

  27. Correa, I. & Raulet, D. H. Binding of diverse peptides to MHC class I molecules inhibits target cell lysis by activated natural killer cells. Immunity 2, 61–71 (1995).

    CAS  PubMed  Google Scholar 

  28. Matsumoto, N., Ribaudo, R. K., Abastado, J. -P., Margulies, D. H. & Yokoyama, W. M. The lectin-like NK cell receptor Ly49A recognizes a carbohydrate-independent epitope on its MHC class I ligand. Immunity 8, 245–254 (1998).

    CAS  PubMed  Google Scholar 

  29. Stoneman, E. R. et al. Cloning and characterization of 5E6(Ly49C), a receptor molecule expressed on a subset of murine natural killer cells. J. Exp. Med. 182, 305–313 (1995).

    CAS  PubMed  Google Scholar 

  30. Mason, L. H. et al. Cloning and functional characteristics of murine large granular lymphocyte-1: a member of the Ly49 gene family (Ly49G2). J. Exp. Med. 182, 293–303 (1995).

    CAS  PubMed  Google Scholar 

  31. Brennan, J., Mahon, G., Mager, D. L., Jefferies, W. A. & Takei, F. Recognition of class I major histocompatibility complex molecules by Ly49: specificities and domain interactions. J. Exp. Med. 183, 1553–1559 (1996).

    CAS  PubMed  Google Scholar 

  32. Hanke, T. et al. Direct assessment of MHC class I binding by seven Ly49 inhibitory NK cell receptors. Immunity 11, 67–77 (1999).

    CAS  PubMed  Google Scholar 

  33. Franksson, L. et al. Peptide dependency and selectivity of the NK cell inhibitory receptor Ly49C. Eur. J. Immunol. 29, 2748–2758 (1999).

    CAS  PubMed  Google Scholar 

  34. Van Beneden, K. et al. Expression of Ly49E and CD94/NKG2 on fetal and adult NK cells. J. Immunol. 166, 4302–4311 (2001).

    CAS  PubMed  Google Scholar 

  35. Mason, L. H. et al. The Ly49D receptor activates murine natural killer cells. J. Exp. Med. 184, 2119–2128 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Smith, H. R. et al. Nonstochastic coexpression of activation receptors on murine natural killer cells. J. Exp. Med. 191, 1341–1354 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Nakamura, M. C. et al. Mouse Ly49D recognizes H–2Dd and activates natural killer cell cytotoxicity. J. Exp. Med. 189, 493–500 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. George, T. C., Ortaldo, J. R., Lemieux, S., Kumar, V. & Bennett, M. Tolerance and alloreactivity of the Ly49D subset of murine NK cells. J. Immunol. 163, 1859–1867 (1999).

    CAS  PubMed  Google Scholar 

  39. Furukawa, H., Iizuka, K., Poursine-Laurent, J., Shastri, N. & Yokoyama, W. M. A ligand for the murine NK activation receptor Ly49D: activation of tolerized NK cells from β2-microglobulin-deficient mice. J. Immunol. 169, 126–136 (2002).

    CAS  PubMed  Google Scholar 

  40. Naper, C. et al. Ly49i2 is an inhibitory rat natural killer cell receptor for an MHC class Ia molecule (RT1-A1c). Eur. J. Immunol. 32, 2031–2036 (2002).

    CAS  PubMed  Google Scholar 

  41. Naper, C. et al. Ly49s3 is a promiscuous activating rat NK cell receptor for nonclassical MHC class I-encoded target ligands. J. Immunol. 169, 22–30 (2002). References 40 and 41 are recent studies on rat NKC receptors.

    CAS  PubMed  Google Scholar 

  42. Westgaard, I. H., Berg, S. F., Orstavik, S., Fossum, S. & Dissen, E. Identification of a human member of the Ly49 multigene family. Eur. J. Immunol. 28, 1839–1846 (1998).

    CAS  PubMed  Google Scholar 

  43. Hackett, J. Jr et al. Origin and differentiation of natural killer cells. II. Functional and morphologic studies of purified NK1.1+ cells. J. Immunol. 136, 3124–3131 (1986).

    PubMed  Google Scholar 

  44. Ryan, J. C., Turck, J., Niemi, E. C., Yokoyama, W. M. & Seaman, W. E. Molecular cloning of the NK1.1 antigen, a member of the NKRP1 family of natural killer cell activation molecules. J. Immunol. 149, 1631–1635 (1992).

    CAS  PubMed  Google Scholar 

  45. Plougastel, B., Matsumoto, K., Dubbelde, C. & Yokoyama, W. M. Analysis of a 1-Mb BAC contig overlapping the mouse Nkrp1 cluster of genes: cloning of three new Nkrp1 members, Nkrp1d, Nkrp1e, and Nkrp1f. Immunogenetics 53, 592–598 (2001).

    CAS  PubMed  Google Scholar 

  46. Karlhofer, F. M. & Yokoyama, W. M. Stimulation of murine natural killer (NK) cells by a monoclonal antibody specific for the NK1.1 antigen. IL-2-activated NK cells possess additional specific stimulation pathways. J. Immunol. 146, 3662–3673 (1991).

    CAS  PubMed  Google Scholar 

  47. Kung, S. K., Su, R. C., Shannon, J. & Miller, R. G. The NKRP1B gene product is an inhibitory receptor on SJL/J NK cells. J. Immunol. 162, 5876–5887 (1999).

    CAS  PubMed  Google Scholar 

  48. Carlyle, J. R. et al. Mouse NKRP1B, a novel NK1.1 antigen with inhibitory function. J. Immunol. 162, 5917–5923 (1999).

    CAS  PubMed  Google Scholar 

  49. Lanier, L. L., Chang, C. & Phillips, J. H. Human NKR-P1A. A disulfide-linked homodimer of the C-type lectin superfamily expressed by a subset of NK and T lymphocytes. J. Immunol. 153, 2417–2428 (1994).

    CAS  PubMed  Google Scholar 

  50. Bendelac, A., Rivera, M. N., Park, S. H. & Roark, J. H. Mouse CD1-specific NK1 T cells: development, specificity, and function. Annu. Rev. Immunol. 15, 535–562 (1997).

    CAS  PubMed  Google Scholar 

  51. Lazetic, S., Chang, C., Houchins, J. P., Lanier, L. L. & Phillips, J. H. Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits. J. Immunol. 157, 4741–4745 (1996). This paper describes that CD94 forms heterodimers with NKG2.

    CAS  PubMed  Google Scholar 

  52. Plougastel, B., Jones, T. & Trowsdale, J. Genomic structure, chromosome location, and alternative splicing of the human NKG2A gene. Immunogenetics 44, 286–291 (1996).

    CAS  PubMed  Google Scholar 

  53. Bellon, T. et al. Triggering of effector functions on a CD8+ T cell clone upon the aggregation of an activatory CD94/kp39 heterodimer. J. Immunol. 162, 3996–4002 (1999).

    CAS  PubMed  Google Scholar 

  54. Plougastel, B. & Trowsdale, J. Cloning of NKG2F, a new member of the NKG2 family of human natural killer cell receptor genes. Eur. J. Immunol. 27, 2835–2839 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  56. 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-1(b). J. Exp. Med. 188, 1841–1848 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Moser, J. M., Gibbs, J., Jensen, P. E. & Lukacher, A. E. CD94–NKG2A receptors regulate antiviral CD8+ T cell responses. Nature Immunol. 3, 189–195 (2002). This paper shows the effect of NKC-encoded receptors on T-cell immunity to an oncogenic virus.

    CAS  Google Scholar 

  58. Vales-Gomez, M., Reyburn, H. T., Erskine, R. A., Lopez-Botet, M. & Strominger, J. L. Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2A and the activating receptor CD94/NKG2C to HLA-E. EMBO J. 18, 4250–4260 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Bauer, S. et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729 (1999). The authors describe how NKG2D and its ligands affect NK- and T-cell functions.

    CAS  PubMed  Google Scholar 

  60. 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  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  62. Wu, J. et al. An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285, 730–732 (1999).

    CAS  PubMed  Google Scholar 

  63. Groh, V. et al. Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nature Immunol. 2, 255–260 (2001).

    CAS  Google Scholar 

  64. Pende, D. et al. Role of NKG2D in tumour cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumours of nonepithelial origin. Eur. J. Immunol. 31, 1076–1086 (2001).

    CAS  PubMed  Google Scholar 

  65. Ho, E. L. et al. Co-stimulation of multiple NK cell activation receptors by NKG2D. J. Immunol. 169, 3667–3675 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  67. Diefenbach, A. et al. Selective associations with signaling molecules determine stimulatory versus costimulatory activity of NKG2D. Nature Immunol. 3, 1142–1149 (2002). References 66 and 67 are recent studies showing that NKG2D isoforms can associate with different signalling chains.

    CAS  Google Scholar 

  68. 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  PubMed  Google Scholar 

  69. Carayannopoulos, L., Naidenko, O., Fremont, D. & Yokoyama, W. M. Cutting edge. Murine UL16-binding protein-like transcript 1: a newly described transcript encoding a high-affinity ligand for murine NKG2D. J. Immunol. 169, 4079–4083 (2002).

    CAS  PubMed  Google Scholar 

  70. Li, P. et al. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nature Immunol. 2, 443–451 (2001).

    CAS  Google Scholar 

  71. Radaev, S., Rostro, B., Brooks, A. G., Colonna, M. & Sun, P. D. Conformational plasticity revealed by the cocrystal structure of NKG2D and its class I MHC-like ligand ULBP3. Immunity 15, 1039–1049 (2001).

    CAS  PubMed  Google Scholar 

  72. Groh, V. et al. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl Acad. Sci. USA 93, 12445–12450 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Girardi, M. et al. Regulation of cutaneous malignancy by γδ T cells. Science 294, 605–609 (2001).

    CAS  PubMed  Google Scholar 

  74. Roda-Navarro, P. et al. Human KLRF1, a novel member of the killer cell lectin-like receptor gene family: molecular characterization, genomic structure, physical mapping to the NK gene complex and expression analysis. Eur. J. Immunol. 30, 568–576 (2000).

    CAS  PubMed  Google Scholar 

  75. Vitale, M. et al. Physical and functional independency of p70 and p58 natural killer (NK) cell receptors for HLA class I: their role in the definition of different groups of alloreactive NK cell clones. Proc. Natl Acad. Sci. USA 93, 1453–1457 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Guthmann, M. D., Tal, M. & Pecht, I. A secretion inhibitory signal transduction molecule on mast cells is another C-type lectin. Proc. Natl Acad. Sci. USA 92, 9397–9401 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Butcher, S., Arney, K. L. & Cook, G. P. MAFA-L, an ITIM-containing receptor encoded by the human NK cell gene complex and expressed by basophils and NK cells. Eur. J. Immunol. 28, 3755–3762 (1998).

    CAS  PubMed  Google Scholar 

  78. Blaser, C., Kaufmann, M. & Pircher, H. Cutting edge. Virus-activated CD8 T cells and lymphokine-activated NK cells express the mast cell function-associated antigen, an inhibitory C-type lectin. J. Immunol. 161, 6451–6454 (1998).

    CAS  PubMed  Google Scholar 

  79. Corral, L., Hanke, T., Vance, R. E., Cado, D. & Raulet, D. H. NK cell expression of the killer cell lectin-like receptor G1 (KLRG1), the mouse homolog of MAFA, is modulated by MHC class I molecules. Eur. J. Immunol. 30, 920–930 (2000).

    CAS  PubMed  Google Scholar 

  80. Robbins, S. H. et al. Cutting edge: inhibitory functions of the killer cell lectin-like receptor G1 molecule during the activation of mouse NK cells. J. Immunol. 168, 2585–2589 (2002).

    CAS  PubMed  Google Scholar 

  81. Boles, K. S., Barten, R., Kumaresan, P. R., Trowsdale, J. & Mathew, P. A. Cloning of a new lectin-like receptor expressed on human NK cells. Immunogenetics 50, 1–7 (1999).

    CAS  PubMed  Google Scholar 

  82. Hamann, J., Montgomery, K. T., Lau, S., Kucherlapati, R. & van Lier, R. A. W. AICL: a new activation-induced antigen encoded by the human NK gene complex. Immunogenetics 45, 295–300 (1997).

    CAS  PubMed  Google Scholar 

  83. Plougastel, B., Dubbelde, C. & Yokoyama, W. M. Cloning of Clr, a new family of lectin-like genes localized between mouse Nkrp1a and Cd69 genes. Immunogenetics 53, 209–214 (2001).

    CAS  PubMed  Google Scholar 

  84. Cebrian, M. et al. Triggering of T cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes. J. Exp. Med. 168, 1621–1637 (1988).

    CAS  PubMed  Google Scholar 

  85. Yokoyama, W. M. et al. Characterization of a cell surface-expressed disulfide-linked dimer involved in murine T cell activation. J. Immunol. 141, 369–376 (1988).

    CAS  PubMed  Google Scholar 

  86. Eichler, W., Ruschpler, P., Wobus, M. & Drossler, K. Differentially induced expression of C-type lectins in activated lymphocytes. J. Cell. Biochem. 81, 201–208 (2001).

    Google Scholar 

  87. Natarajan, K., Dimasi, N., Wang, J., Mariuzza, R. A. & Margulies, D. H. Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu. Rev. Immunol. 20, 853–885 (2002).

    CAS  PubMed  Google Scholar 

  88. Natarajan, K. et al. Interaction of the NK cell inhibitory receptor Ly49A with H–2Dd: identification of a site distinct from the TCR site. Immunity 11, 591–601 (1999).

    CAS  PubMed  Google Scholar 

  89. Boyington, J. C. et al. Structure of CD94 reveals a novel C-type lectin fold: implications for the NK cell-associated CD94/NKG2 receptors. Immunity 10, 75–82 (1999).

    CAS  PubMed  Google Scholar 

  90. Tormo, J., Natarajan, K., Margulies, D. H. & Mariuzza, R. A. Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Nature 402, 623–631 (1999). This study describes a structural analysis of the complex formed between Ly49a and its MHC class I ligand.

    CAS  PubMed  Google Scholar 

  91. Wolan, D. W. et al. Crystal structure of the murine NK cell-activating receptor NKG2D at 1.95 Å. Nature Immunol. 2, 248–254 (2001).

    CAS  Google Scholar 

  92. Li, P., McDermott, G. & Strong, R. K. Crystal structures of RAE-1β and its complex with the activating immunoreceptor NKG2D. Immunity 16, 77–86 (2002).

    CAS  PubMed  Google Scholar 

  93. Matsumoto, N., Yokoyama, W. M., Kojima, S. & Yamamoto, K. The NK cell MHC class I receptor Ly49A detects mutations on H–2Dd inside and outside of the peptide binding groove. J. Immunol. 166, 4422–4428 (2001).

    CAS  PubMed  Google Scholar 

  94. Michaelsson, J., Achour, A., Rolle, A. & Karre, K. MHC class I recognition by NK receptors in the Ly49 family is strongly influenced by the β2-microglobulin subunit. J. Immunol. 166, 7327–7334 (2001).

    CAS  PubMed  Google Scholar 

  95. Wang, J. et al. Binding of the natural killer cell inhibitory receptor Ly49A to its major histocompatibility complex class I ligand. Crucial contacts include both H–2Dd and β2-microglobulin. J. Biol. Chem. 277, 1433–1442 (2002).

    CAS  PubMed  Google Scholar 

  96. Matsumoto, N., Mitsuki, M., Tajima, K., Yokoyama, W. M. & Yamamoto, K. The functional binding site for the C-type lectin-like natural killer cell receptor Ly49A spans three domains of its major histocompatibility complex class I ligand. J. Exp. Med. 193, 147–158 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Dimasi, N. et al. Crystal structure of the Ly49I natural killer cell receptor reveals variability in dimerization mode within the Ly49 family. J. Mol. Biol. 320, 573–585 (2002).

    CAS  PubMed  Google Scholar 

  98. Sundback, J., Achour, A., Michaelsson, J., Lindstrom, H. & Karre, K. NK cell inhibitory receptor Ly49C residues involved in MHC class I binding. J. Immunol. 168, 793–800 (2002).

    CAS  PubMed  Google Scholar 

  99. Diefenbach, A., Jensen, E. R., Jamieson, A. M. & Raulet, D. H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165–171 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Groh, V., Wu, J., Yee, C. & Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734–738 (2002). This paper identifies soluble MIC as a new strategy for tumour evasion.

    CAS  PubMed  Google Scholar 

  101. Yokoyama, W. M. Catch us if you can. Nature 419, 679–680 (2002).

    CAS  PubMed  Google Scholar 

  102. Salih, H. R., Rammensee, H. G. & Steinle, A. Cutting edge: down-regulation of MICA on human tumours by proteolytic shedding. J. Immunol. 169, 4098–4102 (2002).

    CAS  PubMed  Google Scholar 

  103. Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J. & Ploegh, H. L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).

    CAS  PubMed  Google Scholar 

  104. Krmpotic, A. et al. MCMV glycoprotein gp40 confers virus resistance to CD8+ T cells and NK cells in vivo. Nature Immunol. 3, 529–535 (2002).

    CAS  Google Scholar 

  105. Scalzo, A. A., Fitzgerald, N. A., Simmons, A., La Vista, A. B. & Shellam, G. R. Cmv1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J. Exp. Med. 171, 1469–1483 (1990).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  107. Daniels, K. A. et al. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49h. J. Exp. Med. 194, 29–44 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  109. Sjolin, H. et al. Pivotal role of KARAP/DAP12 adaptor molecule in the natural killer cell-mediated resistance to murine cytomegalovirus infection. J. Exp. Med. 195, 825–834 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  111. Smith, H. R. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl Acad. Sci. USA 99, 8826–8831 (2002). References 106–108, 110 and 111 are studies that identify Ly49h as being the factor involved in genetic resistance to MCMV and its ligand.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  113. Mehta, I. K., Smith, H. R. C., Wang, J., Margulies, D. H. & Yokoyama, W. M. A 'chimeric' C57L-derived Ly49 inhibitory receptor resembling the Ly49D activation receptor. Cell. Immunol. 209, 29–41 (2001).

    CAS  PubMed  Google Scholar 

  114. Farrell, H. E. et al. Inhibition of natural killer cells by a cytomegalovirus MHC class I homologue in vivo. Nature 386, 510–514 (1997).

    CAS  PubMed  Google Scholar 

  115. Kavanagh, D. G., Gold, M. C., Wagner, M., Koszinowski, U. H. & Hill, A. B. The multiple immune-evasion genes of murine cytomegalovirus are not redundant: m4 and m152 inhibit antigen presentation in a complementary and cooperative fashion. J. Exp. Med. 194, 967–978 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Paloneva, J. et al. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nature Genet. 25, 357–361 (2000).

    CAS  PubMed  Google Scholar 

  117. Orange, J. S., Fassett, M. S., Koopman, L. A., Boyson, J. E. & Strominger, J. L. Viral evasion of natural killer cells. Nature Immunol. 3, 1006–1012 (2002).

    CAS  Google Scholar 

  118. McMahon, C. W. et al. Viral and bacterial infections induce expression of multiple NK cell receptors in responding CD8+ T cells. J. Immunol. 169, 1444–1452 (2002).

    CAS  PubMed  Google Scholar 

  119. Miller, J. D. et al. CD94/NKG2 expression does not inhibit cytotoxic function of lymphocytic choriomeningitis virus-specific CD8+ T cells. J. Immunol. 169, 693–701 (2002).

    CAS  PubMed  Google Scholar 

  120. Peacock, C. D., Lin, M. Y., Ortaldo, J. R. & Welsh, R. M. The virus-specific and allospecific cytotoxic T-lymphocyte response to lymphocytic choriomeningitis virus is modified in a subpopulation of CD8+ T cells coexpressing the inhibitory major histocompatibility complex class I receptor Ly49G2. J. Virol. 74, 7032–7038 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Assarsson, E. et al. CD8+ T cells rapidly acquire NK1.1 and NK cell-associated molecules upon stimulation in vitro and in vivo. J. Immunol. 165, 3673–3679 (2000).

    CAS  PubMed  Google Scholar 

  122. Brownstein, D. G. & Gras, L. Differential pathogenesis of lethal mousepox in congenic DBA/2 mice implicates natural killer cell receptor NKRP1 in necrotizing hepatitis and the fifth component of complement in recruitment of circulating leukocytes to spleen. Am. J. Pathol. 150, 1407–1420 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Pereira, R. A., Scalzo, A. & Simmons, A. Cutting edge: a NK complex-linked locus governs acute versus latent herpes simplex virus infection of neurons. J. Immunol. 166, 5869–5873 (2001).

    CAS  PubMed  Google Scholar 

  124. Idris, A. H. et al. The natural killer cell complex genetic locus, Chok, encodes Ly49D, a target recognition receptor that activates natural killing. Proc. Natl Acad. Sci. USA 96, 6330–6335 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Dissen, E., Ryan, J. C., Seaman, W. E. & Fossum, S. An autosomal dominant locus, Nka, mapping to the Ly49 region of a rat natural killer (NK) gene complex, controls NK cell lysis of allogeneic lymphocytes. J. Exp. Med. 183, 2197–2207 (1996).

    CAS  PubMed  Google Scholar 

  126. Brown, M. G. et al. Natural killer gene complex (NKC) allelic variability in inbred mice: evidence for NKC haplotypes. Immunogenetics 53, 584–591 (2001).

    CAS  PubMed  Google Scholar 

  127. Lee, S. H. et al. Haplotype mapping indicates two independent origins for the Cmv1s susceptibility allele to cytomegalovirus infection and refines its localization within the Ly49 cluster. Immunogenetics 53, 501–505 (2001). References 126 and 127 describe NKC haplotypes in mice and contain a compendia of markers and typing regimens for distinguishing NKC alleles of many NKC genes in many laboratory mouse strains.

    CAS  PubMed  Google Scholar 

  128. Wilson, M. J. et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc. Natl Acad. Sci. USA 97, 4778–4783 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  131. Raulet, D. H., Vance, R. E. & McMahon, C. W. Regulation of the natural killer cell receptor repertoire. Annu. Rev. Immunol. 19, 291–330 (2001).

    CAS  PubMed  Google Scholar 

  132. Mehta, I. K., Wang, J., Roland, J., Margulies, D. H. & Yokoyama, W. M. Ly49A allelic variation and MHC class I specificity. Immunogenetics 53, 572–583 (2001).

    CAS  PubMed  Google Scholar 

  133. Yokoyama, W. M. Hybrid resistance and the Ly49 family of natural killer cell receptors. J. Exp. Med. 182, 273–277 (1995).

    CAS  PubMed  Google Scholar 

  134. Kaufman, J. et al. The chicken B locus is a minimal essential major histocompatibility complex. Nature 401, 923–925 (1999). This study provides evidence for the apparent linkage of the NKC with the MHC in chickens.

    CAS  PubMed  Google Scholar 

  135. Khalturin, K., Becker, M., Rinkevich, B. & Bosch, T. C. Urochordates and the origin of natural killer cells: identification of a CD94/NKR-P1-related receptor in blood cells of Botryllus. Proc. Natl Acad. Sci. USA 100, 622–627 (2003). This recent paper identifies the presence of an NKC-related molecule in tunicates.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Afonso, C. L. et al. The genome of fowlpox virus. J. Virol. 74, 3815–3831 (2000). This is one of many poxvirus genome papers that highlights the presence of open reading frames for NKC-related molecules.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Bull, C. et al. The centromeric part of the human NK gene complex: linkage of LOX1 and LY49L with the CD94/NKG2 region. Genes Immun 1, 280–287 (2000).

    CAS  PubMed  Google Scholar 

  138. Sawamura, T. et al. An endothelial receptor for oxidized low-density lipoprotein. Nature 386, 73–77 (1997).

    CAS  PubMed  Google Scholar 

  139. Delneste, Y. et al. Involvement of LOX1 in dendritic cell-mediated antigen cross-presentation. Immunity 17, 353–362 (2002).

    CAS  PubMed  Google Scholar 

  140. Sobanov, Y. et al. A novel cluster of lectin-like receptor genes expressed in monocytic, dendritic and endothelial cells maps close to the NK receptor genes in the human NK gene complex. Eur. J. Immunol. 31, 3493–3503 (2001).

    CAS  PubMed  Google Scholar 

  141. Brown, G. D. et al. Dectin1 is a major β-glucan receptor on macrophages. J. Exp. Med. 196, 407–412 (2002). References 139 and 141 describe innate non-NK-cell functions of NKC molecules.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Kung, S. K., Su, R. C., Shannon, J. & Miller, R. G. The NKRP1B gene product is an inhibitory receptor on SJL/J NK cells. J. Immunol. 162, 5876–5887 (1999).

    CAS  PubMed  Google Scholar 

  143. Colonna, M., Samaridis, J. & Angman, L. Molecular characterization of two novel C-type lectin-like receptors, one of which is selectively expressed in human dendritic cells. Eur. J. Immunol. 30, 697–704 (2000).

    CAS  PubMed  Google Scholar 

  144. George, T. C., Mason, L. H., Ortaldo, J. R., Kumar, V. & Bennett, M. Positive recognition of MHC class I molecules by the Ly49D receptor of murine NK cells. J. Immunol. 162, 2035–2043 (1999).

    CAS  PubMed  Google Scholar 

  145. O'Callaghan, C. A., Cerwenka, A., Willcox, B. E., Lanier, L. L. & Bjorkman, P. J. Molecular competition for NKG2D: H60 and RAE1 compete unequally for NKG2D with dominance of H60. Immunity 15, 201–211 (2001).

    CAS  PubMed  Google Scholar 

  146. Carayannopoulos, L. N. et al. Ligands for murine NKG2D display heterogeneous binding behaviour. Eur. J. Immunol. 32, 597–605 (2002).

    CAS  PubMed  Google Scholar 

  147. Vales-Gomez, M., Reyburn, H. T., Mandelboim, M. & Strominger, J. L. Kinetics of interaction of HLA-C ligands with natural killer cell inhibitory receptors. Immunity 9, 337–344 (1998).

    CAS  PubMed  Google Scholar 

  148. Chapman, T. L., Heikeman, A. P. & Bjorkman, P. J. The inhibitory receptor LIR1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 11, 603–613 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge M. Colonna for discussion of unpublished work, A. Diefenbach and D. Raulet for sharing an unpublished manuscript, and L. Carayannopoulos, T. French and H. Smith for critical evaluation of this manuscript. Work in the Yokoyama laboratory is supported by the Barnes-Jewish Hospital Research Foundation, National Institutes of Health and Howard Hughes Medical Institute. We apologize to our colleagues for not being able to cite additional studies due to space constraints.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wayne M. Yokoyama.

Related links

Related links

DATABASES

LocusLink

CD94

DAP10

DAP12

H-60

HLA-E

KLRF1

KLRG1

Ly49

Ly49A

MICA

MICB

NKG2

NKRP1

Qa-1

Rae1

ULBP

FURTHER INFORMATION

Natural killer gene complex website

Glossary

NATURAL KILLER CELLS

(NK cells). Lymphocytes that do not express the T-cell receptor or B-cell receptor and mediate natural killing against prototypical NK-cell-sensitive targets — K562 (human) and YAC-1 (mouse). In humans, NK cells are typically CD56+CD3, and they are NK1.1+CD3 in the C57BL/6 mouse strain and generally DX5+CD3 in other mouse strains. Recent studies indicate that NKG2D might be a useful marker for all CD3 NK cells in various mouse strains.

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIF

(ITIM). This motif is found in the cytoplasmic domains of the inhibitory receptors. After ligand binding, the ITIM (Val/Ile-Xaa-Tyr-Xaa-Xaa-Leu/Val) becomes tyrosine phosphorylated, which recruits and activates phosphatases.

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF

(ITAM). B-, T- and natural killer-cell receptors are non-covalently associated with transmembrane proteins that contain one or more ITAMs. The motif (Asp/Glu-Xaa-Xaa-Tyr-Xaa-Xaa-Leu/Ile-Xaa(6–8)-Tyr-Xaa-Xaa-Leu/Ile) is tyrosine phosphorylated after engagement of the ligand-binding subunits, which triggers a cascade of intracellular events that result in cell activation.

SYNTENIC REGION

A genomic DNA fragment in another species that contains orthologous genes.

ORTHOLOGOUS GENES

Genes present in a different species that are derived from a common ancestral gene.

NATURAL KILLER T CELLS

(NKT cells). A subpopulation of T cells that expresses both NK- and T-cell markers. In the C57BL/6 mouse strain, NKT cells express the NK1.1 (Nkrp1c) molecule and the T-cell receptor (TCR). Some NKT cells recognize CD1d-associated lipid antigens and express a restricted repertoire of TCRs. After TCR stimulation of naive mice, NKT cells rapidly produce interleukin-4 and interferon-γ.

HAPLOTYPE

A chromosomal segment from similar or related ancestors that contains identical alleles in a region of genetically linked loci.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yokoyama, W., Plougastel, B. Immune functions encoded by the natural killer gene complex. Nat Rev Immunol 3, 304–316 (2003). https://doi.org/10.1038/nri1055

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1055

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing