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:

A new self: MHC-class-I-independent Natural-killer-cell self-tolerance

Key Points

  • Natural killer (NK) cell cytotoxicity is regulated by inhibitory receptors that bind self-MHC class I molecules. The absence of MHC class I expression causes lysis of cells, as described by the 'missing-self' hypothesis.

  • Some aspects of NK-cell biology cannot be explained by the regulation of self-tolerance through MHC class I molecules alone, implying the existence of non-MHC-binding inhibitory receptors.

  • 2B4 is a prototypical MHC-independent inhibitory receptor. It inhibits NK-cell responses to CD48-expressing cells in mice, as well as in the absence of SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) in humans. This inhibition protects against NK-cell autoreactivity.

  • Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) ensures NK-cell tolerance in MHC-class-I-deficient humans.

  • Several other NK-cell inhibitory receptors recognize diverse ligands that are markers of 'self'. These receptors include some NK-cell receptor protein 1 (NKR-P1)-family members, sialic-acid-binding immunoglobulin-like lectins (SIGLECs) and glycoprotein 49 B1 (gp49B1).

  • Non-MHC-binding inhibitory receptors regulate NK-cell responses in disease states, including infection, cancer and autoimmunity. These receptors might provide new targets for improving NK-cell responses, possibly leading to better treatments for such diseases.

Abstract

A fundamental tenet of the immune system is the requirement for lymphocytes to respond to transformed or infected cells while remaining tolerant of normal cells. Natural killer (NK) cells discriminate between self and non-self by monitoring the expression of MHC class I molecules. According to the 'missing-self' hypothesis, cells that express self-MHC class I molecules are protected from NK cells, but those that lack this self-marker are eliminated by NK cells. Recent work has revealed that there is another system of NK-cell inhibition, which is independent of MHC class I molecules. Newly discovered NK-cell inhibitory receptors that have non-MHC-molecule ligands broaden the definition of self as seen by NK cells.

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-cell self-tolerance and the 'missing-self' hypothesis.
Figure 2: NK-cell inhibitory receptors that have non-MHC-molecule ligands.
Figure 3: Proximal signalling pathways of 2B4: activating and inhibitory.

Similar content being viewed by others

References

  1. 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  PubMed  PubMed Central  Google Scholar 

  2. Tato, C. M. et al. Innate production of IFN-γ by NK cells is independent of epigenetic modification of the IFN-γ promoter. J. Immunol. 173, 1514–1517 (2004).

    CAS  PubMed  Google Scholar 

  3. Walker, L. S. & Abbas, A. K. The enemy within: keeping self-reactive T cells at bay in the periphery. Nature Rev. Immunol. 2, 11–19 (2002).

    CAS  Google Scholar 

  4. 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 

  5. Karre, 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).

    CAS  PubMed  Google Scholar 

  6. Tay, C. H., Szomolanyi-Tsuda, E. & Welsh, R. M. Control of infections by NK cells. Curr. Top. Microbiol. Immunol. 230, 193–220 (1998).

    CAS  PubMed  Google Scholar 

  7. Yu, Y. Y., Kumar, V. & Bennett, M. Murine natural killer cells and marrow graft rejection. Annu. Rev. Immunol. 10, 189–213 (1992).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. 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  PubMed  PubMed Central  Google Scholar 

  10. Lee, N. et al. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc. Natl Acad. Sci. USA 95, 5199–5204 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. Chapman, T. L., Heikeman, A. P. & Bjorkman, P. J. The inhibitory receptor LIR-1 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 

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

    CAS  PubMed  Google Scholar 

  14. 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  PubMed  PubMed Central  Google Scholar 

  15. de la Salle, H. et al. Homozygous human TAP peptide transporter mutation in HLA class I deficiency. Science 265, 237–241 (1994).

    CAS  PubMed  Google Scholar 

  16. Zimmer, J. et al. Activity and phenotype of natural killer cells in peptide transporter (TAP)-deficient patients (type I bare lymphocyte syndrome). J. Exp. Med. 187, 117–122 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Dorfman, J. R., Zerrahn, J., Coles, M. C. & Raulet, D. H. The basis for self-tolerance of natural killer cells in β2-microglobulin and TAP-1 mice. J. Immunol. 159, 5219–5225 (1997).

    CAS  PubMed  Google Scholar 

  18. Salcedo, M. et al. Fine tuning of natural killer cell specificity and maintenance of self tolerance in MHC class I-deficient mice. Eur. J. Immunol. 28, 1315–1321 (1998).

    CAS  PubMed  Google Scholar 

  19. Markel, G. et al. The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients. Blood 103, 1770–1778 (2004). This study shows that increased CEACAM1 expression prevents NK-cell autoreactivity in TAP2-deficient patients.

    CAS  PubMed  Google Scholar 

  20. Vitale, M. et al. Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells. Blood 99, 1723–1729 (2002). This paper shows that triggering receptors in TAP2-deficient patients are functional, and the authors suggest a role for non-MHC-binding inhibitory receptors in self-tolerance.

    CAS  PubMed  Google Scholar 

  21. Furukawa, H., Iizuka, K., Poursine-Laurent, J., Shastri, N. & Yokoyama, W. M. A ligand for the murine NK activation receptor Ly-49D: activation of tolerized NK cells from β2-microglobulin-deficient mice. J. Immunol. 169, 126–136 (2002).

    CAS  PubMed  Google Scholar 

  22. Fernandez, N. C. et al. A subset of natural killer cells achieve self-tolerance without expressing inhibitory receptors specific for self MHC molecules. Blood 22 Feb 2005 (10.1182/blood-2004-1108-3156).

    Google Scholar 

  23. Yu, Y. Y. et al. The role of Ly49A and 5E6 (Ly49C) molecules in hybrid resistance mediated by murine natural killer cells against normal T cell blasts. Immunity 4, 67–76 (1996).

    CAS  PubMed  Google Scholar 

  24. Liu, J. et al. Ly49I NK cell receptor transgene inhibition of rejection of H2b mouse bone marrow transplants. J. Immunol. 164, 1793–1799 (2000).

    CAS  PubMed  Google Scholar 

  25. Sivakumar, P. V. et al. Expression of functional CD94/NKG2A inhibitory receptors on fetal NK1.1+Ly-49 cells: a possible mechanism of tolerance during NK cell development. J. Immunol. 162, 6976–6980 (1999).

    CAS  PubMed  Google Scholar 

  26. Dorfman, J. R. & Raulet, D. H. Acquisition of Ly49 receptor expression by developing natural killer cells. J. Exp. Med. 187, 609–618 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Vance, R. E., Jamieson, A. M., Cado, D. & Raulet, D. H. Implications of CD94 deficiency and monoallelic NKG2A expression for natural killer cell development and repertoire formation. Proc. Natl Acad. Sci. USA 99, 868–873 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sivori, S. et al. Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation. Proc. Natl Acad. Sci. USA 99, 4526–4531 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lee, K. M. et al. 2B4 acts as a non-major histocompatibility complex binding inhibitory receptor on mouse natural killer cells. J. Exp. Med. 199, 1245–1254 (2004). This paper, together with references 38 and 39, characterizes 2B4-deficient mice, showing that 2B4 inhibits NK cells and that this outcome is not regulated by SAP.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Boles, K. S., Stepp, S. E., Bennett, M., Kumar, V. & Mathew, P. A. 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol. Rev. 181, 234–249 (2001).

    CAS  PubMed  Google Scholar 

  31. Kubota, K. A structurally variant form of the 2B4 antigen is expressed on the cell surface of mouse mast cells. Microbiol. Immunol. 46, 589–592 (2002).

    CAS  PubMed  Google Scholar 

  32. Munitz, A. et al. 2B4 (CD244) is expressed and functional on human eosinophils. J. Immunol. 174, 110–118 (2005).

    CAS  PubMed  Google Scholar 

  33. McNerney, M. E., Lee, K. M. & Kumar, V. 2B4 (CD244) is a non-MHC binding receptor with multiple functions on natural killer cells and CD8+ T cells. Mol. Immunol. 42, 489–494 (2005).

    CAS  PubMed  Google Scholar 

  34. Engel, P., Eck, M. J. & Terhorst, C. The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nature Rev. Immunol. 3, 813–821 (2003).

    CAS  Google Scholar 

  35. Brown, M. H. et al. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. J. Exp. Med. 188, 2083–2090 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Valiante, N. M. & Trinchieri, G. Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes. J. Exp. Med. 178, 1397–1406 (1993).

    CAS  PubMed  Google Scholar 

  37. Garni-Wagner, B. A., Purohit, A., Mathew, P. A., Bennett, M. & Kumar, V. A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells. J. Immunol. 151, 60–70 (1993).

    CAS  PubMed  Google Scholar 

  38. Mooney, J. M. et al. The murine NK receptor 2B4 (CD244) exhibits inhibitory function independent of signaling lymphocytic activation molecule-associated protein expression. J. Immunol. 173, 3953–3961 (2004).

    CAS  PubMed  Google Scholar 

  39. Vaidya, S. V. et al. Targeted disruption of the 2B4 gene in mice reveals an in vivo role of 2B4 (CD244) in the rejection of B16 melanoma cells. J. Immunol. 174, 800–807 (2005).

    CAS  PubMed  Google Scholar 

  40. Lee, K. M. et al. The NK cell receptor 2B4 augments antigen-specific T cell cytotoxicity through CD48 ligation on neighboring T cells. J. Immunol. 170, 4881–4885 (2003).

    CAS  PubMed  Google Scholar 

  41. Assarsson, E. et al. NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions. J. Immunol. 173, 174–180 (2004).

    CAS  PubMed  Google Scholar 

  42. Kambayashi, T., Assarsson, E., Chambers, B. J. & Ljunggren, H. G. Regulation of CD8+ T cell proliferation by 2B4/CD48 interactions. J. Immunol. 167, 6706–6710 (2001).

    CAS  PubMed  Google Scholar 

  43. Tangye, S. G., Phillips, J. H., Lanier, L. L. & Nichols, K. E. Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. J. Immunol. 165, 2932–2936 (2000).

    CAS  PubMed  Google Scholar 

  44. Tangye, S. G., Cherwinski, H., Lanier, L. L. & Phillips, J. H. 2B4-mediated activation of human natural killer cells. Mol. Immunol. 37, 493–501 (2000).

    CAS  PubMed  Google Scholar 

  45. Parolini, S. et al. X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein–Barr virus-infected cells. J. Exp. Med. 192, 337–346 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Glimcher, L., Shen, F. W. & Cantor, H. Identification of a cell-surface antigen selectively expressed on the natural killer cell. J. Exp. Med. 145, 1–9 (1977).

    CAS  PubMed  Google Scholar 

  47. Koo, G. C. & Peppard, J. R. Establishment of monoclonal anti-NK-1.1 antibody. Hybridoma 3, 301–303 (1984).

    CAS  PubMed  Google Scholar 

  48. Arase, N. et al. Association with FcRγ is essential for activation signal through NKR-P1 (CD161) in natural killer (NK) cells and NK1.1+ T cells. J. Exp. Med. 186, 1957–1963 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Carlyle, J. R. et al. Mouse NKR-P1B, a novel NK1.1 antigen with inhibitory function. J. Immunol. 162, 5917–5923 (1999).

    CAS  PubMed  Google Scholar 

  50. Kung, S. K., Su, R. C., Shannon, J. & Miller, R. G. The NKR-P1B gene product is an inhibitory receptor on SJL/J NK cells. J. Immunol. 162, 5876–5887 (1999).

    CAS  PubMed  Google Scholar 

  51. Iizuka, K., Naidenko, O. V., Plougastel, B. F., Fremont, D. H. & Yokoyama, W. M. Genetically linked C-type lectin-related ligands for the NKRP1 family of natural killer cell receptors. Nature Immunol. 4, 801–807 (2003).

    CAS  Google Scholar 

  52. Carlyle, J. R. et al. Missing self-recognition of Ocil/Clr-b by inhibitory NKR-P1 natural killer cell receptors. Proc. Natl Acad. Sci. USA 101, 3527–3532 (2004). References 51 and 52 identify CLRs as ligands for receptors of the NKR-P1 family.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

  54. Yokoyama, W. M. & Plougastel, B. F. Immune functions encoded by the natural killer gene complex. Nature Rev. Immunol. 3, 304–316 (2003).

    CAS  Google Scholar 

  55. Zhou, H. et al. A novel osteoblast-derived C-type lectin that inhibits osteoclast formation. J. Biol. Chem. 276, 14916–14923 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  57. 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 

  58. Mathew, P. A. et al. The LLT1 receptor induces IFN-γ production by human natural killer cells. Mol. Immunol. 40, 1157–1163 (2004).

    CAS  PubMed  Google Scholar 

  59. Hammarstrom, S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin. Cancer Biol. 9, 67–81 (1999).

    CAS  PubMed  Google Scholar 

  60. Moller, M. J., Kammerer, R., Grunert, F. & von Kleist, S. Biliary glycoprotein (BGP) expression on T cells and on a natural-killer-cell sub-population. Int. J. Cancer 65, 740–745 (1996).

    CAS  PubMed  Google Scholar 

  61. Markel, G. et al. The critical role of residues 43R and 44Q of carcinoembryonic antigen cell adhesion molecules-1 in the protection from killing by human NK cells. J. Immunol. 173, 3732–3739 (2004).

    CAS  PubMed  Google Scholar 

  62. Singer, B. B. et al. Carcinoembryonic antigen-related cell adhesion molecule 1 expression and signaling in human, mouse, and rat leukocytes: evidence for replacement of the short cytoplasmic domain isoform by glycosylphosphatidylinositol-linked proteins in human leukocytes. J. Immunol. 168, 5139–5146 (2002).

    CAS  PubMed  Google Scholar 

  63. Kammerer, R., Stober, D., Singer, B. B., Obrink, B. & Reimann, J. Carcinoembryonic antigen-related cell adhesion molecule 1 on murine dendritic cells is a potent regulator of T cell stimulation. J. Immunol. 166, 6537–6544 (2001).

    CAS  PubMed  Google Scholar 

  64. Markel, G. et al. CD66a interactions between human melanoma and NK cells: a novel class I MHC-independent inhibitory mechanism of cytotoxicity. J. Immunol. 168, 2803–2810 (2002). This was one of the first reports on the inhibition of NK cells by CEACAM1, which led to much further research.

    CAS  PubMed  Google Scholar 

  65. Markel, G. et al. Biological function of the soluble CEACAM1 protein and implications in TAP2-deficient patients. Eur. J. Immunol. 34, 2138–2148 (2004).

    CAS  PubMed  Google Scholar 

  66. Svenberg, T. et al. Serum level of biliary glycoprotein I, a determinant of cholestasis, of similar use as γ-glutamyltranspeptidase. Scand. J. Gastroenterol. 16, 817–824 (1981).

    CAS  PubMed  Google Scholar 

  67. Crocker, P. R. & Varki, A. Siglecs, sialic acids and innate immunity. Trends Immunol. 22, 337–342 (2001).

    CAS  PubMed  Google Scholar 

  68. Angata, T. & Varki, A. Chemical diversity in the sialic acids and related α-keto acids: an evolutionary perspective. Chem. Rev. 102, 439–469 (2002).

    CAS  PubMed  Google Scholar 

  69. Falco, M. et al. Identification and molecular cloning of p75/AIRM1, a novel member of the sialoadhesin family that functions as an inhibitory receptor in human natural killer cells. J. Exp. Med. 190, 793–802 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Nicoll, G. et al. Identification and characterization of a novel siglec, siglec-7, expressed by human natural killer cells and monocytes. J. Biol. Chem. 274, 34089–34095 (1999).

    CAS  PubMed  Google Scholar 

  71. Ito, A., Handa, K., Withers, D. A., Satoh, M. & Hakomori, S. Binding specificity of siglec7 to disialogangliosides of renal cell carcinoma: possible role of disialogangliosides in tumor progression. FEBS Lett. 504, 82–86 (2001).

    CAS  PubMed  Google Scholar 

  72. Yamaji, T., Teranishi, T., Alphey, M. S., Crocker, P. R. & Hashimoto, Y. A small region of the natural killer cell receptor, Siglec-7, is responsible for its preferred binding to α2,8-disialyl and branched α2,6-sialyl residues. A comparison with Siglec-9. J. Biol. Chem. 277, 6324–6332 (2002).

    CAS  PubMed  Google Scholar 

  73. Nicoll, G. et al. Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec-7-dependent and -independent mechanisms. Eur. J. Immunol. 33, 1642–1648 (2003). This paper shows that GD3 expression by target cells inhibits NK cells through interaction with SIGLEC7.

    CAS  PubMed  Google Scholar 

  74. Urmacher, C., Cordon-Cardo, C. & Houghton, A. N. Tissue distribution of GD3 ganglioside detected by mouse monoclonal antibody R24. Am. J. Dermatopathol. 11, 577–581 (1989).

    CAS  PubMed  Google Scholar 

  75. Kniep, B., Flegel, W. A., Northoff, H. & Rieber, E. P. CDw60 glycolipid antigens of human leukocytes: structural characterization and cellular distribution. Blood 82, 1776–1786 (1993).

    CAS  PubMed  Google Scholar 

  76. Ikehara, Y., Ikehara, S. K. & Paulson, J. C. Negative regulation of T cell receptor signaling by Siglec-7 (p70/AIRM) and Siglec-9. J. Biol. Chem. 279, 43117–43125 (2004).

    CAS  PubMed  Google Scholar 

  77. Avril, T., Floyd, H., Lopez, F., Vivier, E. & Crocker, P. R. The membrane-proximal immunoreceptor tyrosine-based inhibitory motif is critical for the inhibitory signaling mediated by siglecs-7 and -9, CD33-related siglecs expressed on human monocytes and NK cells. J. Immunol. 173, 6841–6849 (2004).

    CAS  PubMed  Google Scholar 

  78. Zhang, J. Q., Nicoll, G., Jones, C. & Crocker, P. R. Siglec-9, a novel sialic acid binding member of the immunoglobulin superfamily expressed broadly on human blood leukocytes. J. Biol. Chem. 275, 22121–22126 (2000).

    CAS  PubMed  Google Scholar 

  79. Zhang, J. Q., Biedermann, B., Nitschke, L. & Crocker, P. R. The murine inhibitory receptor mSiglec-E is expressed broadly on cells of the innate immune system whereas mSiglec-F is restricted to eosinophils. Eur. J. Immunol. 34, 1175–1184 (2004).

    CAS  PubMed  Google Scholar 

  80. Ulyanova, T., Shah, D. D. & Thomas, M. L. Molecular cloning of MIS, a myeloid inhibitory siglec, that binds protein-tyrosine phosphatases SHP-1 and SHP-2. J. Biol. Chem. 276, 14451–14458 (2001).

    CAS  PubMed  Google Scholar 

  81. van den Berg, T. K., Yoder, J. A. & Litman, G. W. On the origins of adaptive immunity: innate immune receptors join the tale. Trends Immunol. 25, 11–16 (2004).

    CAS  PubMed  Google Scholar 

  82. Piccio, L. et al. Adhesion of human T cells to antigen-presenting cells through SIRPβ2–CD47 interaction costimulates T cell proliferation. Blood 105, 2421–2427 (2005).

    CAS  PubMed  Google Scholar 

  83. Brooke, G., Holbrook, J. D., Brown, M. H. & Barclay, A. N. Human lymphocytes interact directly with CD47 through a novel member of the signal regulatory protein (SIRP) family. J. Immunol. 173, 2562–2570 (2004).

    CAS  PubMed  Google Scholar 

  84. Oldenborg, P. -A. et al. Role of CD47 as a marker of self on red blood cells. Science 288, 2051–2054 (2000).

    CAS  PubMed  Google Scholar 

  85. Blazar, B. R. et al. CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells. J. Exp. Med. 194, 541–550 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Katz, H. R. Inhibitory receptors and allergy. Curr. Opin. Immunol. 14, 698–704 (2002).

    CAS  PubMed  Google Scholar 

  87. Wang, L. L., Mehta, I. K., LeBlanc, P. A. & Yokoyama, W. M. Mouse natural killer cells express gp49B1, a structural homologue of human killer inhibitory receptors. J. Immunol. 158, 13–17 (1997).

    CAS  PubMed  Google Scholar 

  88. Wang, L. L., Chu, D. T., Dokun, A. O. & Yokoyama, W. M. Inducible expression of the gp49B inhibitory receptor on NK cells. J. Immunol. 164, 5215–5220 (2000).

    CAS  PubMed  Google Scholar 

  89. Castells, M. C. et al. gp49B1–αvβ3 interaction inhibits antigen-induced mast cell activation. Nature Immunol. 2, 436–442 (2001).

    CAS  Google Scholar 

  90. Wilder, R. L. Integrin αVβ3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases. Ann. Rheum. Dis. 61, ii96–ii99 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Rojo, S. et al. Natural killer cells and mast cells from gp49B null mutant mice are functional. Mol. Cell. Biol. 20, 7178–7182 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Gu, X. et al. The gp49B1 inhibitory receptor regulates the IFN-γ responses of T cells and NK cells. J. Immunol. 170, 4095–4101 (2003). This study shows that, compared with cells from normal mice, gp49B1-deficient NK cells and T cells produce more IFN-γ ex vivo , following in vivo viral infection.

    CAS  PubMed  Google Scholar 

  93. Abramson, J., Xu, R. & Pecht, I. An unusual inhibitory receptor — the mast cell function-associated antigen (MAFA). Mol. Immunol. 38, 1307–1313 (2002).

    CAS  PubMed  Google Scholar 

  94. Robbins, S. H. et al. 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 

  95. 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 

  96. Meyaard, L. et al. LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes. Immunity 7, 283–290 (1997).

    CAS  PubMed  Google Scholar 

  97. Thorley-Lawson, D. A., Schooley, R. T., Bhan, A. K. & Nadler, L. M. Epstein–Barr virus superinduces a new human B cell differentiation antigen (B-LAST 1) expressed on transformed lymphoblasts. Cell 30, 415–425 (1982).

    CAS  PubMed  Google Scholar 

  98. Biron, C. A., Byron, K. S. & Sullivan, J. L. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731–1735 (1989).

    CAS  PubMed  Google Scholar 

  99. 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 

  100. Afonso, C. L. et al. The genome of fowlpox virus. J. Virol. 74, 3815–3831 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Shchelkunov, S. N. et al. The genomic sequence analysis of the left and right species-specific terminal region of a cowpox virus strain reveals unique sequences and a cluster of intact ORFs for immunomodulatory and host range proteins. Virology 243, 432–460 (1998).

    CAS  PubMed  Google Scholar 

  102. Wilcock, D., Duncan, S. A., Traktman, P., Zhang, W. H. & Smith, G. L. The vaccinia virus A4OR gene product is a nonstructural, type II membrane glycoprotein that is expressed at the cell surface. J. Gen. Virol. 80, 2137–2148 (1999).

    CAS  PubMed  Google Scholar 

  103. Cameron, C. et al. The complete DNA sequence of myxoma virus. Virology 264, 298–318 (1999).

    CAS  PubMed  Google Scholar 

  104. Neilan, J. G. et al. An African swine fever virus ORF with similarity to C-type lectins is non-essential for growth in swine macrophages in vitro and for virus virulence in domestic swine. J. Gen. Virol. 80, 2693–2697 (1999).

    CAS  PubMed  Google Scholar 

  105. Voigt, S., Sandford, G. R., Ding, L. & Burns, W. H. Identification and characterization of a spliced C-type lectin-like gene encoded by rat cytomegalovirus. J. Virol. 75, 603–611 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Lindberg, F. P., Gresham, H. D., Schwarz, E. & Brown, E. J. Molecular cloning of integrin-associated protein: an immunoglobulin family member with multiple membrane-spanning domains implicated in αVβ3-dependent ligand binding. J. Cell Biol. 123, 485–496 (1993).

    CAS  PubMed  Google Scholar 

  107. Campbell, I. G., Freemont, P. S., Foulkes, W. & Trowsdale, J. An ovarian tumor marker with homology to vaccinia virus contains an IgV-like region and multiple transmembrane domains. Cancer Res. 52, 5416–5420 (1992).

    CAS  PubMed  Google Scholar 

  108. Tseng, C. T. & Klimpel, G. R. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J. Exp. Med. 195, 43–49 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Crotta, S. et al. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J. Exp. Med. 195, 35–41 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Razi, N. & Varki, A. Cryptic sialic acid binding lectins on human blood leukocytes can be unmasked by sialidase treatment or cellular activation. Glycobiology 9, 1225–1234 (1999).

    CAS  PubMed  Google Scholar 

  111. Razi, N. & Varki, A. Masking and unmasking of the sialic acid-binding lectin activity of CD22 (Siglec-2) on B lymphocytes. Proc. Natl Acad. Sci. USA 95, 7469–7474 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Boulton, I. C. & Gray-Owen, S. D. Neisserial binding to CEACAM1 arrests the activation and proliferation of CD4+ T lymphocytes. Nature Immunol. 3, 229–236 (2002). This paper shows that the binding of bacteria to CEACAM1 at the surface of T cells inhibits T-cell functions.

    CAS  Google Scholar 

  113. Dveksler, G. S. et al. Several members of the mouse carcinoembryonic antigen-related glycoprotein family are functional receptors for the coronavirus mouse hepatitis virus-A59. J. Virol. 67, 1–8 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Virji, M., Watt, S. M., Barker, S., Makepeace, K. & Doyonnas, R. The N-domain of the human CD66a adhesion molecule is a target for Opa proteins of Neisseria meningitidis and Neisseria gonorrhoeae. Mol. Microbiol. 22, 929–939 (1996).

    CAS  PubMed  Google Scholar 

  115. Leusch, H. G., Drzeniek, Z., Markos-Pusztai, Z. & Wagener, C. Binding of Escherichia coli and Salmonella strains to members of the carcinoembryonic antigen family: differential binding inhibition by aromatic α-glycosides of mannose. Infect. Immun. 59, 2051–2057 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Hill, D. J. & Virji, M. A novel cell-binding mechanism of Moraxella catarrhalis ubiquitous surface protein UspA: specific targeting of the N-domain of carcinoembryonic antigen-related cell adhesion molecules by UspA1. Mol. Microbiol. 48, 117–129 (2003).

    CAS  PubMed  Google Scholar 

  117. Virji, M. et al. Carcinoembryonic antigens are targeted by diverse strains of typable and non-typable Haemophilus influenzae. Mol. Microbiol. 36, 784–795 (2000).

    CAS  PubMed  Google Scholar 

  118. Garrido, F. et al. Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol. Today 18, 89–95 (1997).

    CAS  PubMed  Google Scholar 

  119. Demanet, C. et al. Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack? Blood 103, 3122–3130 (2004).

    CAS  PubMed  Google Scholar 

  120. Saito, S. et al. Expression of globe-series gangliosides in human renal cell carcinoma. Jpn J. Cancer Res. 88, 652–659 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Plunkett, T. A. & Ellis, P. A. CEACAM1: a marker with a difference or more of the same? J. Clin. Oncol. 20, 4273–4275 (2002).

    PubMed  Google Scholar 

  122. Thies, A. et al. CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J. Clin. Oncol. 20, 2530–2536 (2002).

    CAS  PubMed  Google Scholar 

  123. Laack, E. et al. Expression of CEACAM1 in adenocarcinoma of the lung: a factor of independent prognostic significance. J. Clin. Oncol. 20, 4279–4284 (2002).

    PubMed  Google Scholar 

  124. Kammerer, R. et al. The tumour suppressor gene CEACAM1 is completely but reversibly downregulated in renal cell carcinoma. J. Pathol. 204, 258–267 (2004).

    CAS  PubMed  Google Scholar 

  125. Pende, D. et al. Analysis of the receptor–ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the poliovirus receptor (CD155) and nectin-2 (CD112). Blood 105, 2066–2073 (2005).

    CAS  PubMed  Google Scholar 

  126. Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002). This study shows the clinical benefits of NK-cell alloreactivity.

    CAS  PubMed  Google Scholar 

  127. Moffett-King, A. Natural killer cells and pregnancy. Nature Rev. Immunol. 2, 656–663 (2002).

    CAS  Google Scholar 

  128. Markel, G. et al. Pivotal role of CEACAM1 protein in the inhibition of activated decidual lymphocyte functions. J. Clin. Invest. 110, 943–953 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Blazar, B. R. et al. A critical role for CD48 antigen in regulating alloengraftment and lymphohematopoietic recovery after bone marrow transplantation. Blood 92, 4453–4463 (1998).

    CAS  PubMed  Google Scholar 

  130. Vitale, C. et al. Analysis of the activating receptors and cytolytic function of human natural killer cells undergoing in vivo differentiation after allogeneic bone marrow transplantation. Eur. J. Immunol. 34, 455–460 (2004).

    CAS  PubMed  Google Scholar 

  131. Smith, G. M., Biggs, J., Norris, B., Anderson-Stewart, P. & Ward, R. Detection of a soluble form of the leukocyte surface antigen CD48 in plasma and its elevation in patients with lymphoid leukemias and arthritis. J. Clin. Immunol. 17, 502–509 (1997).

    CAS  PubMed  Google Scholar 

  132. Wandstrat, A. E. et al. Association of extensive polymorphisms in the SLAM/CD2 gene cluster with murine lupus. Immunity 21, 769–780 (2004).

    CAS  PubMed  Google Scholar 

  133. Speckman, R. A. et al. Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Hum. Genet. 112, 34–41 (2003).

    CAS  PubMed  Google Scholar 

  134. Cantoni, C. et al. Molecular and functional characterization of IRp60, a member of the immunoglobulin superfamily that functions as an inhibitory receptor in human NK cells. Eur. J. Immunol. 29, 3148–3159 (1999).

    CAS  PubMed  Google Scholar 

  135. Iijima, H. et al. Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1. J. Exp. Med. 199, 471–482 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Boulanger, L. M. & Shatz, C. J. Immune signalling in neural development, synaptic plasticity and disease. Nature Rev. Neurosci. 5, 521–531 (2004).

    CAS  Google Scholar 

  137. Malisan, F. & Testi, R. GD3 ganglioside and apoptosis. Biochim. Biophys. Acta 1585, 179–187 (2002).

    CAS  PubMed  Google Scholar 

  138. Backstrom, E., Chambers, B. J., Kristensson, K. & Ljunggren, H. G. Direct NK cell-mediated lysis of syngenic dorsal root ganglia neurons in vitro. J. Immunol. 165, 4895–4900 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Abbas, M. Alegre, B. Jabri and R. Taniguchi for helpful comments regarding the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Vinay Kumar.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

2B4

CD47

CD48

CEACAM1

CLR-B

gp49B1

αVβ3-integrin

NKR-P1D

SIGLEC7

SIRP-β2

FURTHER INFORMATION

Vinay Kumar's homepage

Glossary

CENTRAL TOLERANCE

Self-tolerance that is created at the level of the central lymphoid organs. Developing T cells, in the thymus, and developing B cells, in the bone marrow, that strongly recognize self-antigen must undergo further rearrangement of antigen-receptor genes to become self-tolerant, or they face deletion. NK cells, which differentiate in the bone marrow, are thought to upregulate the expression of inhibitory receptors until they are self-tolerant and are allowed to migrate to the periphery.

PERIPHERAL TOLERANCE

Self-tolerance that is mediated in the peripheral tissues. These mechanisms control potentially self-reactive lymphocytes that have escaped central-tolerance mechanisms.

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIFS

(ITIMs). ITIMs have the amino-acid sequence Ile/Val-X-Tyr-X-X-Leu/Val, where X denotes any amino acid. They recruit inhibitory phosphatases after phosphorylation of their tyrosine residue.

C-TYPE LECTIN

Lectins are carbohydrate-binding molecules, and C-type lectins were named for their ability to bind calcium. C-type- lectin-like molecules, such as many of the natural-killer-cell receptors, are disulphide-linked homodimers that have sequence homology to C-type lectins; however, they do not bind calcium, and they often recognize proteins instead of carbohydrates.

LEADER PEPTIDES

Hydrophobic amino-acid sequences that signal for proteins to translocate to the endoplasmic reticulum. The leader peptide is cleaved before a protein is transported from the cell.

TRANSPORTER ASSOCIATED WITH ANTIGEN PROCESSING

(TAP). TAP1 and TAP2 form a heterodimer in the membrane of the endoplasmic reticulum. The TAP1–TAP2 complex transports peptides from the cytoplasm to the endoplasmic reticulum, where peptides can be loaded onto MHC class I molecules. Without these peptides, MHC class I molecules are unstable and are much less likely to transit to the cell surface or to remain there.

β2-MICROGLOBULIN

2m). A single immunoglobulin-like domain that non-covalently associates with the main polypeptide chain of MHC class I molecules. In the absence of β2m, MHC class I molecules are unstable and are therefore found at very low levels at the cell surface.

SIGNALLING LYMPHOCYTIC ACTIVATION MOLECULE

(SLAM). A receptor that is expressed by several types of immune cell. Receptors in the SLAM subfamily of CD2 proteins, which includes 2B4, have similar sequences, have immunoreceptor tyrosine-based switch motifs (ITSMs) and bind SLAM-associated protein (SAP).

IMMUNORECEPTOR TYROSINE-BASED SWITCH MOTIFS

(ITSMs). ITSMs have the amino-acid sequence Thr-X-Tyr-X-X-Val/Ile, where X denotes any amino acid. They recruit many of the same signalling molecules as immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activation motifs (ITAMs), but they also recruit SAP (signalling lymphocytic activation molecule (SLAM)-associated protein).

SRC-HOMOLOGY-2 DOMAIN

(SH2 domain). A domain that is found in signalling molecules. It binds phosphorylated tyrosine residues and thereby mediates protein–protein interactions.

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIFS

(ITAMs). ITAMs have the amino-acid sequence Asp/Glu-X-X-Tyr-X-X-Leu/Ile-X6–8-Tyr-X-X-Leu/Ile, where X denotes any amino acid. They recruit activating signalling molecules after tyrosine phosphorylation.

X-LINKED LYMPHOPROLIFERATIVE SYNDROME

(XLP). Patients with XLP have complicated immune dysfunctions, often triggered by infection with Epstein–Barr virus. Many patients develop fatal B-cell lymphoproliferation. The gene that encodes SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) has been found to be mutated in these patients.

GLYCOSYLPHOSPHATIDYL-INOSITOL LINKED

(GPI linked). A lipid modification of a protein that anchors the protein to the plasma membrane.

V-SET IMMUNOGLOBULIN DOMAIN

An immunoglobulin domain is a characteristic protein fold that is present in all members of the immunoglobulin superfamily. On the basis of size and sequence, V-set immunoglobulin domains are similar to the variable regions of antibody molecules.

C2-SET IMMUNOGLOBULIN DOMAINS

C2-set immunoglobulin domains are similar to the constant regions of antibody molecules, as defined on the basis of size and sequence.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumar, V., McNerney, M. A new self: MHC-class-I-independent Natural-killer-cell self-tolerance. Nat Rev Immunol 5, 363–374 (2005). https://doi.org/10.1038/nri1603

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1603

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