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:

Current perspectives of natural killer cell education by MHC class I molecules

Nature Reviews Immunology volume 10, pages 724–734 (2010)Cite this article

Subjects

Key Points

  • Natural killer (NK) cells are negatively controlled by MHC class I molecules, which are recognized through inhibitory receptors. The main type of inhibitory receptors are Ly49 receptors (in mice) and killer cell immunoglobulin-like receptors (KIRs; in humans). When target cells downregulate MHC class I molecule expression, they have a 'missing-self' phenotype that is recognized by NK cells and results in their activation.

  • MHC class I molecules are also necessary for the functional development of NK cells. This process is termed 'NK cell education' and has also been referred to as 'licensing' or 'arming'. NK cells that lack inhibitory receptors or only express inhibitory receptors for which no MHC class I ligands are expressed in vivo are uneducated and hyporesponsive.

  • Successful NK cell education leads to the full functional development of NK cells, including the ability to mediate cytotoxicity and cytokine secretion. Individual NK cells are also sensitive to the strength of inhibitory input during education and set thresholds for activation that match this inhibitory input.

  • The signalling mechanisms that link the inhibitory input to functional development during NK cell education are unknown. It has also not been determined whether NK cell education is restricted to haematopoietic niches in the body and requires interactions with a particular cell, or whether it can occur everywhere after interaction with any surrounding self cell.

  • Individual Ly49 receptors and KIRs are expressed in a stochastic and independent manner on NK cells. This leads to the formation of a unique 'NK cell repertoire' in each individual, which is characterized by the coexistence of several NK cell subsets, each expressing from zero to five receptors.

  • The composition of the NK cell repertoire is determined by several factors, most of which have yet to be identified. In mice, the MHC repertoire affects the composition of the final Ly49 repertoire and thus contributes to NK cell education. A similar effect of the MHC repertoire on the human NK cell repertoire is less obvious.

  • NK cells may contribute to clinically important graft-versus-leukaemia effects following stem cell transplantation, in particular against acute myeloid leukaemia. A better understanding of NK cell education may help clinicians to find the optimal donor for each recipient, based on an analysis of their KIRs and MHC repertoire.

Abstract

From the early days of natural killer (NK) cell research, it was clear that MHC genes controlled the specificity of mouse NK cell-dependent responses, such as the ability to reject transplanted allogeneic bone marrow and to kill tumour cells. Although several mechanisms that are involved in this 'education' process have been clarified, most of the mechanisms have still to be identified. Here, we review the current understanding of the processes that are involved in NK cell education, including how the host MHC class I molecules regulate responsiveness and receptor repertoire formation in NK cells and the signalling pathways that are involved.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Measures of NK cell education.
Figure 2: Models for NK cell education.
Figure 3: Three layers of inhibitory influences in NK cells.

Similar content being viewed by others

References

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

    CAS  PubMed  PubMed Central  Google Scholar 

  2. O'Leary, J. G., Goodarzi, M., Drayton, D. L. & von Andrian, U. H. T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nature Immunol. 7, 507–516 (2006).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  5. Khakoo, S. I. & Carrington, M. KIR and disease: a model system or system of models? Immunol. Rev. 214, 186–201 (2006).

    CAS  PubMed  Google Scholar 

  6. Johansson, S., Berg, L., Hall, H. & Höglund, P. NK cells: elusive players in autoimmunity. Trends Immunol. 26, 613–618 (2005).

    CAS  PubMed  Google Scholar 

  7. 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 

  8. Ljunggren, H. G. et al. Empty MHC class I molecules come out in the cold. Nature 346, 476–480 (1990).

    CAS  PubMed  Google Scholar 

  9. Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002).

    CAS  PubMed  Google Scholar 

  10. Cudkowicz, G. & Stimpfling, J. H. Induction of immunity and of unresponsiveness to parental marrow grafts in adult F-1 hybrid mice. Nature 204, 450–453 (1964).

    CAS  PubMed  Google Scholar 

  11. Cudkowicz, G. Genetic control of bone marrow graft rejection. I. Determinant-specific difference of reactivity in two pairs of inbred mouse strains. J. Exp. Med. 134, 281–293 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cudkowicz, G. & Stimpfling, J. H. Deficient growth of C57BL marrow cells transplanted in F1 hybrid mice. Association with the histocompatibility-2 locus. Immunology 7, 291–306 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kiessling, R. et al. Evidence for a similar or common mechanism for natural killer cell activity and resistance to hemopoietic grafts. Eur. J. Immunol. 7, 655–663 (1977).

    CAS  PubMed  Google Scholar 

  14. Höglund, P. et al. Natural resistance against lymphoma grafts conveyed by H-2Dd transgene to C57BL mice. J. Exp. Med. 168, 1469–1474 (1988).

    PubMed  Google Scholar 

  15. Ohlen, C. et al. Prevention of allogeneic bone marrow graft rejection by H-2 transgene in donor mice. Science 246, 666–668 (1989).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. Johansson, S. et al. Natural killer cell education in mice with single or multiple major histocompatibility complex class I molecules. J. Exp. Med. 201, 1145–1155 (2005). This study was the first to show that different MHC class I alleles have a unique 'educating impact' on the NK cell system, suggesting that NK cell education may be a quantitative process.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Fernandez, N. C. et al. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood 105, 4416–4423 (2005). References 17, 18 and 20 were the first to link MHC class I-dependent functional maturation with inhibitory receptors and to demonstrate the presence of uneducated NK cells in normal individuals.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Moretta, L. & Moretta, A. Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J. 23, 255–259 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. 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 

  26. 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 

  27. Lopez-Botet, M., Angulo, A. & Guma, M. Natural killer cell receptors for major histocompatibility complex class I and related molecules in cytomegalovirus infection. Tissue Antigens 63, 195–203 (2004).

    CAS  PubMed  Google Scholar 

  28. Ciccone, E. et al. Self class I molecules protect normal cells from lysis mediated by autologous natural killer cells. Eur. J. Immunol. 24, 1003–1006 (1994).

    CAS  PubMed  Google Scholar 

  29. Valiante, N. M. et al. Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity 7, 739–751 (1997).

    CAS  PubMed  Google Scholar 

  30. Bix, M. et al. Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature 349, 329–331 (1991).

    CAS  PubMed  Google Scholar 

  31. Höglund, P. et al. Recognition of beta 2-microglobulin-negative (beta 2m-) T-cell blasts by natural killer cells from normal but not from beta 2m− mice: nonresponsiveness controlled by beta 2m− bone marrow in chimeric mice. Proc. Natl Acad. Sci. USA 88, 10332–10336 (1991).

    PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. 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 

  34. Brodin, P., Lakshmikanth, T., Johansson, S., Karre, K. & Höglund, P. The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells. Blood 113, 2434–2441 (2009). References 34 and 49 were the first to show that the strength of inhibitory input by MHC class I molecules through inhibitory Ly49 receptors determines the threshold for activation of NK cells.

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  36. Tay, C. H., Welsh, R. M. & Brutkiewicz, R. R. NK cell response to viral infections in beta 2-microglobulin-deficient mice. J. Immunol. 154, 780–789 (1995). References 35 and 36 showed that 'uneducated' NK cells can clear MCMV infection, questioning the importance of education for some NK cell-mediated functions in vivo.

    CAS  PubMed  Google Scholar 

  37. Lucas, M., Schachterle, W., Oberle, K., Aichele, P. & Diefenbach, A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26, 503–517 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Chaix, J. et al. Cutting edge: priming of NK cells by IL-18. J. Immunol. 181, 1627–1631 (2008).

    CAS  PubMed  Google Scholar 

  39. Peterson, M. E. & Long, E. O. Inhibitory receptor signaling via tyrosine phosphorylation of the adaptor Crk. Immunity 29, 578–588 (2008). This study provided new insights into inhibitory signalling and showed that CRK was phosphorylated by the kinase ABL1 downstream of inhibitory receptors, identifying potential ways by which inhibitory receptor signalling might affect the activating signals that are needed for NK cell education.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Yokoyama, W. M. Inhibitory receptors signal activation. Immunity 29, 515–517 (2008).

    CAS  PubMed  Google Scholar 

  41. Yokoyama, W. M. & Kim, S. Licensing of natural killer cells by self-major histocompatibility complex class, I. Immunol. Rev. 214, 143–154 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  43. Doucey, M. A. et al. Cis association of Ly49A with MHC class I restricts natural killer cell inhibition. Nature Immunol. 5, 328–336 (2004).

    CAS  Google Scholar 

  44. Zimmer, J., Ioannidis, V. & Held, W. H-2D ligand expression by Ly49A+ natural killer (NK) cells precludes ligand uptake from environmental cells: implications for NK cell function. J. Exp. Med. 194, 1531–1539 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Chalifour, A. et al. A Role for cis interaction between the inhibitory Ly49A receptor and MHC class I for natural killer cell education. Immunity 30, 337–347 (2009). This study presented a new model for NK cell education based on cis interactions between Ly49 receptors and MHC class I molecules on the NK cell membrane.

    CAS  PubMed  Google Scholar 

  46. Andersson, K. E., Williams, G. S., Davis, D. M. & Höglund, P. Quantifying the reduction in accessibility of the inhibitory NK cell receptor Ly49A caused by binding MHC class I proteins in cis. Eur. J. Immunol. 37, 516–527 (2007).

    CAS  PubMed  Google Scholar 

  47. Back, J. et al. Distinct conformations of Ly49 natural killer cell receptors mediate MHC class I recognition in trans and cis. Immunity 31, 598–608 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  50. Brodin, P. & Höglund, P. Beyond licensing and disarming: a quantitative view on NK-cell education. Eur. J. Immunol. 38, 2934–2937 (2008).

    CAS  PubMed  Google Scholar 

  51. Lanier, L. L. Up on the tightrope: natural killer cell activation and inhibition. Nature Immunol. 9, 495–502 (2008).

    CAS  Google Scholar 

  52. Stebbins, C. C. et al. Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity. Mol. Cell Biol. 23, 6291–6299 (2003). This study provided the first evidence that inhibitory receptor signalling could terminate activating signals by dephosphorylating VAV1, a common factor in both inhibitory and activating pathways.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Bryceson, Y. T., March, M. E., Ljunggren, H. G. & Long, E. O. Activation, coactivation, and costimulation of resting human natural killer cells. Immunol. Rev. 214, 73–91 (2006).

    CAS  PubMed  Google Scholar 

  54. Kim, H. S., Das, A., Gross, C. C., Bryceson, Y. T. & Long, E. O. Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase. Immunity 32, 175–186 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Yawata, M. et al. MHC class I-specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response. Blood 112, 2369–2380 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Fauriat, C., Ivarsson, M. A., Ljunggren, H. G., Malmberg, K. J. & Michaelsson, J. Education of human natural killer cells by activating killer cell immunoglobulin-like receptors. Blood 115, 1166–1174 (2010).

    CAS  PubMed  Google Scholar 

  57. Lowin-Kropf, B., Kunz, B., Beermann, F. & Held, W. Impaired natural killing of MHC class I-deficient targets by NK cells expressing a catalytically inactive form of SHP-1. J. Immunol. 165, 1314–1321 (2000).

    CAS  PubMed  Google Scholar 

  58. Jonsson, A. H., Yang, L., Kim, S., Taffner, S. M. & Yokoyama, W. M. Effects of MHC class I alleles on licensing of Ly49A+ NK cells. J. Immunol. 184, 3424–3432 (2010).

    CAS  PubMed  Google Scholar 

  59. Yusa, S. & Campbell, K. S. Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) can play a direct role in the inhibitory function of killer cell Ig-like receptors in human NK cells. J. Immunol. 170, 4539–4547 (2003).

    CAS  PubMed  Google Scholar 

  60. 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 

  61. Fortenbery, N. R. et al. SHIP influences signals from CD48 and MHC class I ligands that regulate NK cell homeostasis, effector function, and repertoire formation. J. Immunol. 184, 5065–5074 (2010).

    CAS  PubMed  Google Scholar 

  62. Shultz, L. D., Rajan, T. V. & Greiner, D. L. Severe defects in immunity and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase deficiency. Trends Biotechnol. 15, 302–307 (1997).

    CAS  Google Scholar 

  63. Tsui, F. W., Martin, A., Wang, J. & Tsui, H. W. Investigations into the regulation and function of the SH2 domain-containing protein-tyrosine phosphatase, SHP-1. Immunol. Res. 35, 127–136 (2006).

    CAS  PubMed  Google Scholar 

  64. Jonsson, A. H. & Yokoyama, W. M. Natural killer cell tolerance licensing and other mechanisms. Adv. Immunol. 101, 27–79 (2009).

    CAS  PubMed  Google Scholar 

  65. Di Santo, J. P. Natural killer cells: diversity in search of a niche. Nature Immunol. 9, 473–475 (2008).

    CAS  Google Scholar 

  66. Saleh, A. et al. Identification of probabilistic transcriptional switches in the Ly49 gene cluster: a eukaryotic mechanism for selective gene activation. Immunity 21, 55–66 (2004).

    CAS  PubMed  Google Scholar 

  67. Davies, G. E. et al. Identification of bidirectional promoters in the human KIR genes. Genes Immun. 8, 245–253 (2007).

    CAS  PubMed  Google Scholar 

  68. Andersson, S., Fauriat, C., Malmberg, J. A., Ljunggren, H. G. & Malmberg, K. J. KIR acquisition probabilities are independent of self-HLA class I ligands and increase with cellular KIR expression. Blood 114, 95–104 (2009).

    CAS  PubMed  Google Scholar 

  69. Johansson, S. et al. Probing natural killer cell education by Ly49 receptor expression analysis and computational modelling in single MHC class I mice. PLoS One 4, e6046 (2009).

    PubMed  PubMed Central  Google Scholar 

  70. Held, W., Dorfman, J. R., Wu, M. F. & Raulet, D. H. Major histocompatibility complex class I-dependent skewing of the natural killer cell Ly49 receptor repertoire. Eur. J. Immunol. 26, 2286–2292 (1996).

    CAS  PubMed  Google Scholar 

  71. Salcedo, M. et al. Altered expression of Ly49 inhibitory receptors on natural killer cells from MHC class I-deficient mice. J. Immunol. 158, 3174–3180 (1997). References 70 and 71 showed a role for MHC class I molecules in the shaping of the inhibitory receptor repertoire.

    CAS  PubMed  Google Scholar 

  72. Hanke, T., Takizawa, H. & Raulet, D. H. MHC-dependent shaping of the inhibitory Ly49 receptor repertoire on NK cells: evidence for a regulated sequential model. Eur. J. Immunol. 31, 3370–3379 (2001).

    CAS  PubMed  Google Scholar 

  73. Lowin-Kropf, B., Kunz, B., Schneider, P. & Held, W. A role for the src family kinase Fyn in NK cell activation and the formation of the repertoire of Ly49 receptors. Eur. J. Immunol. 32, 773–782 (2002).

    CAS  PubMed  Google Scholar 

  74. Whittaker, G. C. et al. Analysis of the linker for activation of T cells and the linker for activation of B cells in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire. Blood 112, 2869–2877 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Coudert, J. D., Scarpellino, L., Gros, F., Vivier, E. & Held, W. Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways. Blood 111, 3571–3578 (2008).

    CAS  PubMed  Google Scholar 

  76. Oppenheim, D. E. et al. Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nature Immunol. 6, 928–937 (2005).

    CAS  Google Scholar 

  77. Wiemann, K. et al. Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo. J. Immunol. 175, 720–729 (2005).

    CAS  PubMed  Google Scholar 

  78. Tripathy, S. K. et al. Continuous engagement of a self-specific activation receptor induces NK cell tolerance. J. Exp. Med. 205, 1829–1841 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Sun, J. C. & Lanier, L. L. Tolerance of NK cells encountering their viral ligand during development. J. Exp. Med. 205, 1819–1828 (2008). References 76–79 provided evidence for induced hyporesponsiveness following continuous stimulation of activating NK cell receptors by a transgenically expressed ligand in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  81. Fauriat, C. et al. Estimation of the size of the alloreactive NK cell repertoire: studies in individuals homozygous for the group A KIR haplotype. J. Immunol. 181, 6010–6019 (2008).

    CAS  PubMed  Google Scholar 

  82. Fahlen, L., Lendahl, U. & Sentman, C. L. MHC class I-Ly49 interactions shape the Ly49 repertoire on murine NK cells. J. Immunol. 166, 6585–6592 (2001).

    CAS  PubMed  Google Scholar 

  83. Raulet, D. H. et al. Specificity, tolerance and developmental regulation of natural killer cells defined by expression of class I-specific Ly49 receptors. Immunol. Rev. 155, 41–52 (1997).

    CAS  PubMed  Google Scholar 

  84. Kim, S. et al. HLA alleles determine differences in human natural killer cell responsiveness and potency. Proc. Natl Acad. Sci. USA 105, 3053–3058 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Di Santo, J. P. Natural killer cell developmental pathways: a question of balance. Annu. Rev. Immunol. 24, 257–286 (2006).

    CAS  PubMed  Google Scholar 

  86. Cella, M. et al. Differential requirements for Vav proteins in DAP10- and ITAM-mediated NK cell cytotoxicity. J. Exp. Med. 200, 817–823 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Malarkannan, S. et al. Bcl10 plays a divergent role in NK cell-mediated cytotoxicity and cytokine generation. J. Immunol. 179, 3752–3762 (2007).

    CAS  PubMed  Google Scholar 

  88. Gross, O. et al. Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-κB and MAPK activation to selectively control cytokine production. Blood 112, 2421–2428 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Hara, H. et al. Cell type-specific regulation of ITAM-mediated NF-κB activation by the adaptors, CARMA1 and CARD9. J. Immunol. 181, 918–930 (2008).

    CAS  PubMed  Google Scholar 

  90. Chiesa, S. et al. Multiplicity and plasticity of natural killer cell signaling pathways. Blood 107, 2364–2372 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Bloch-Queyrat, C. et al. Regulation of natural cytotoxicity by the adaptor SAP and the Src-related kinase Fyn. J. Exp. Med. 202, 181–192 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Mason, L. H., Willette-Brown, J., Taylor, L. S. & McVicar, D. W. Regulation of Ly49D/DAP12 signal transduction by Src-family kinases and CD45. J. Immunol. 176, 6615–6623 (2006).

    CAS  PubMed  Google Scholar 

  93. Shier, P. et al. Impaired immune responses toward alloantigens and tumor cells but normal thymic selection in mice deficient in the β2 integrin leukocyte function-associated antigen-1. J. Immunol. 157, 5375–5386 (1996).

    CAS  PubMed  Google Scholar 

  94. Schmits, R. et al. LFA-1-deficient mice show normal CTL responses to virus but fail to reject immunogenic tumor. J. Exp. Med. 183, 1415–1426 (1996).

    CAS  PubMed  Google Scholar 

  95. Matsumoto, G., Nghiem, M. P., Nozaki, N., Schmits, R. & Penninger, J. M. Cooperation between CD44 and LFA-1/CD11a adhesion receptors in lymphokine-activated killer cell cytotoxicity. J. Immunol. 160, 5781–5789 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  97. Horng, T., Bezbradica, J. S. & Medzhitov, R. NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway. Nature Immunol. 8, 1345–1352 (2007).

    CAS  Google Scholar 

  98. Tassi, I. et al. DAP10 associates with Ly49 receptors but contributes minimally to their expression and function in vivo. Eur. J. Immunol. 39, 1129–1135 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Zompi, S. et al. NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases. Nature Immunol. 4, 565–572 (2003).

    CAS  Google Scholar 

  100. Bakker, A. B. et al. DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13, 345–353 (2000).

    CAS  PubMed  Google Scholar 

  101. Huntington, N. D., Xu, Y., Nutt, S. L. & Tarlinton, D. M. A requirement for CD45 distinguishes Ly49D-mediated cytokine and chemokine production from killing in primary natural killer cells. J. Exp. Med. 201, 1421–1433 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hesslein, D. G., Takaki, R., Hermiston, M. L., Weiss, A. & Lanier, L. L. Dysregulation of signaling pathways in CD45-deficient NK cells leads to differentially regulated cytotoxicity and cytokine production. Proc. Natl Acad. Sci. USA 103, 7012–7017 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Yamada, H., Kishihara, K., Kong, Y. Y. & Nomoto, K. Enhanced generation of NK cells with intact cytotoxic function in CD45 exon 6-deficient mice. J. Immunol. 157, 1523–1528 (1996).

    CAS  PubMed  Google Scholar 

  104. Cruz-Munoz, M. E., Dong, Z., Shi, X., Zhang, S. & Veillette, A. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nature Immunol. 10, 297–305 (2009).

    CAS  Google Scholar 

  105. Roncagalli, R. et al. Negative regulation of natural killer cell function by EAT-2, a SAP-related adaptor. Nature Immunol. 6, 1002–1010 (2005).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Zafirova, B. et al. Altered NK cell development and enhanced NK cell-mediated resistance to mouse cytomegalovirus in NKG2D-deficient mice. Immunity 31, 270–282 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Colucci, F. et al. Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases. Nature Immunol. 3, 288–294 (2002).

    CAS  Google Scholar 

  110. Regunathan, J. et al. Differential and nonredundant roles of phospholipase Cγ2 and phospholipase Cγ1 in the terminal maturation of NK cells. J. Immunol. 177, 5365–5376 (2006).

    CAS  PubMed  Google Scholar 

  111. Caraux, A. et al. Phospholipase C-γ2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells. Blood 107, 994–1002 (2006).

    CAS  PubMed  Google Scholar 

  112. Kim, N. et al. The p110δ catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion. Blood 110, 3202–3208 (2007).

    CAS  PubMed  Google Scholar 

  113. Tassi, I. et al. p110γ and p110δ phosphoinositide 3-kinase signaling pathways synergize to control development and functions of murine NK cells. Immunity 27, 214–227 (2007).

    CAS  PubMed  Google Scholar 

  114. Guo, H., Samarakoon, A., Vanhaesebroeck, B. & Malarkannan, S. The p110 δ of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J. Exp. Med. 205, 2419–2435 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Awasthi, A. et al. Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells. Genes Immun. 9, 522–535 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Tomasello, E. et al. Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice. Immunity 13, 355–364 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to express their thanks to all members of the Höglund group for important scientific input, to E. Long for critical reading of the manuscript and to K. Kärre and all members of his group for stimulating discussions. Work in our group is supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Karolinska Institutet, the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), the Marianne and Marcus Wallenberg Foundation and the Mary Bevé Foundation.

Author information

Authors and Affiliations

  1. Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Box 280, Stockholm, SE-171 77, Sweden

    Petter Höglund & Petter Brodin

Authors
  1. Petter Höglund
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Petter Brodin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Petter Höglund.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 table

Genetic modulation of molecules involved in activating receptor signalling in mouse NK cells (PDF 185 kb)

Related links

Related links

FURTHER INFORMATION

Petter Höglund's homepage

Glossary

Killer cell immunoglobulin-like receptors

(KIRs). These receptors, which are encoded on human chromosome 19, are expressed by natural killer cell subsets and by a minor population of T cells. Inhibitory KIRs have locus and allele specificity for MHC class I molecules.

Missing-self recognition

The recognition and attack of cells that do not express MHC class I molecules — in other words, that are 'missing self' — by natural killer cells. This provides a surveillance mechanism to detect virally infected or transformed cells that downregulate MHC class I expression.

Graft-versus-leukaemia

An immune response that is mounted by the transplanted cells against the tumour cells of the host. This response is one of the reasons why allogeneic transplants can be curative for cancer.

β2-microglobulin

(β2m). 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.

Anergy

A state of T cell unresponsiveness following stimulation with an antigen. It can be induced by stimulation with a large amount of a specific antigen in the absence of engagement of co-stimulatory molecules.

E3 ubiquitin ligase

The enzyme that is required to attach the molecular tag ubiquitin to proteins that are destined for degradation by the proteasomal complex.

Motheaten viable mice

(mev/mev mice). Mice that have a mutation in the coding region of the catalytic domain of SH2-domain-containing protein tyrosine phosphatase 1 (SHP1), which results in two aberrant loss-of-function proteins (one of 67 kDa and one of 71 kDa). These mice develop severe combined immunodeficiency and systemic autoimmunity.

Antibody-dependent cell-mediated cytotoxicity

A mechanism by which natural killer (NK) cells kill other cells, such as virus-infected target cells that are coated with antibodies. The Fc portions of the coating antibodies interact with the Fc receptor (FcγRIII; also known as CD16) that is expressed by NK cells, thereby initiating a signalling cascade that results in the release of cytotoxic granules (containing perforin and granzyme B), which induce apoptosis of the antibody-coated cell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Höglund, P., Brodin, P. Current perspectives of natural killer cell education by MHC class I molecules. Nat Rev Immunol 10, 724–734 (2010). https://doi.org/10.1038/nri2835

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2835

This article is cited by

Search

Advanced 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