Natural killer cell activation in mice and men: different triggers for similar weapons?


The signaling pathways that regulate B and T lymphocytes are remarkably conserved between humans and mice. However, recent evidence suggests that the pathways regulating natural killer (NK) cell activation may actually differ between these two species. We discuss the controversies in the field and propose that this divergence could be deceptive: despite some clear differences between human and mouse NK cell receptors, the many ways of activating NK cells and their functions may well be conserved.

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Figure 1: Molecules that regulate NK cell activation.
Figure 2: Major biochemical pathways for NK cell activation.
Figure 3: Chromosomal localization of genes for NK receptors and ligands.


  1. 1

    Ravetch, J.V. & Lanier, L.L. Immune inhibitory receptors. Science 290, 84–89 (2000).

    CAS  Article  Google Scholar 

  2. 2

    Long, E.O. et al. Inhibition of natural killer cell activation signals by killer cell immunoglobulin-like receptors (CD158). Immunol. Rev. 181, 223–233 (2001).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Kiessling, R., Klein, E. & Wigzell, H. “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur. J. Immunol. 5, 112–117 (1975).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Herberman, R.B., Nunn, M.E. & Lavrin, D.H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int. J. Cancer 16, 216–229 (1975).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Basse, P.H., Whiteside, T.L., Chambers, W. & Herberman, R.B. Therapeutic activity of NK cells against tumors. Int. Rev. Immunol. 20, 439–501 (2001).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Fehniger, T.A. & Caligiuri, M.A. Ontogeny and expansion of human natural killer cells: clinical implications. Int. Rev. Immunol. 20, 503–534 (2001).

    CAS  Article  PubMed  Google Scholar 

  7. 7

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

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Downward, J. The ins and outs of signalling. Nature 411, 759–762 (2001).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Brumbaugh, K.M. et al. Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity. J. Exp. Med. 186, 1965–1974 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Colucci, F. et al. Redundant role of the Syk protein tyrosine kinase in mouse NK cell differentiation. J. Immunol. 163, 1769–1774 (1999).

    CAS  PubMed  Google Scholar 

  11. 11

    Zhang, W. et al. Essential role of LAT in T cell development. Immunity 10, 323–332 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Jevremovic, D. et al. Cutting edge: a role for the adaptor protein LAT in human NK cell-mediated cytotoxicity. J. Immunol. 162, 2453–2456 (1999).

    CAS  PubMed  Google Scholar 

  13. 13

    Lanier, L.L. On guard–activating NK cell receptors. Nature Immunol. 2, 23–27 (2001).

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 15

    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  Article  Google Scholar 

  16. 16

    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  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    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  Google Scholar 

  18. 18

    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  Article  PubMed  Google Scholar 

  19. 19

    Sutherland, C.L., Chalupny, N.J. & Cosman D. The UL16-binding proteins, a novel family of MHC class I-related ligands for NKG2D, activate natural killer cell functions. Immunol. Rev. 181, 185–192 (2001).

    CAS  Article  Google Scholar 

  20. 20

    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  Article  Google Scholar 

  21. 21

    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  Article  Google Scholar 

  22. 22

    Mandelboim, O. et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409, 1055–1060 (2001).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Hornung, V. et al. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J. Immunol. 168, 4531–4537 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Billadeau, D.D. & Leibson, P.J. ITAMs versus ITIMs: striking a balance during cell regulation. J. Clin. Invest. 109, 161–168 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Lanier, L.L. NK cell receptors. Annu. Rev. Immunol. 16, 359–393 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Moretta, A. et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu. Rev. Immunol. 19, 197–223 (2001).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Leibson, P.J. Signal transduction during natural killer activation: inside the mind of a killer. Immunity 6, 655–661 (1997).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Takai, T., Li, M., Sylvestre, D., Clynes, R. & Ravetch, J.V. FcRγ chain deletion results in pleiotropic effector cell defects. Cell, 76, 519–529 (1994).

    CAS  Article  Google Scholar 

  29. 29

    van Oers, N.S., Lowin-Kropf, B., Finlay, D., Connolly, K. & Weiss, A. αβ T cell development is abolished in mice lacking both Lck and Fyn protein tyrosine kinases. Immunity 5, 429–436 (1996).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Chu, D.H. et al. The Syk protein tyrosine kinase can function independently of CD45 or Lck in T cell antigen receptor signaling. EMBO J. 15, 6251–6261 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    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  Google Scholar 

  32. 32

    Negishi, I. et al. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435–438 (1995).

    CAS  Article  Google Scholar 

  33. 33

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

    CAS  Article  Google Scholar 

  34. 34

    Ting, A.T., Karnitz, L.M., Schoon, R.A., Abraham, R.T. & Leibson, P.J. Fcγ receptor activation induces the tyrosine phosphorylation of both phospholipase C (PLC)-γ 1 and PLC-γ 2 in natural killer cells. J. Exp. Med. 176, 1751–1755 (1992).

    CAS  Article  Google Scholar 

  35. 35

    Wang, D. et al. Phospholipase Cg2 is essential in the functions of B cell and several Fc receptors. Immunity 13, 25–35 (2000).

    Article  Google Scholar 

  36. 36

    Billadeau, D.D., Mackie, S.M., Schoon, R.A. & Leibson, P.J. The Rho family guanine nucleotide exchange factor Vav-2 regulates the development of cell-mediated cytotoxicity. J. Exp. Med. 192, 381–392 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Colucci, F. et al. Functional dichotomy in natural killer cell signaling: Vav1-dependent and -independent mechanisms. J. Exp. Med. 193, 1413–1424 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Binstadt, B.A. et al. SLP-76 is a direct substrate of SHP-1 recruited to killer cell inhibitory receptors. J. Biol. Chem. 273, 27518–27523 (1998).

    CAS  Article  Google Scholar 

  39. 39

    Clements, J.L. et al. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Science 281, 416–419 (1998).

    CAS  Article  Google Scholar 

  40. 40

    Smith, K.M., Wu, J., Bakker, A.B., Phillips, J.H. & Lanier, L.L. Ly-49D and Ly-49H associate with mouse DAP12 and form activating receptors. J. Immunol. 161, 7–10 (1998).

    CAS  Google Scholar 

  41. 41

    Cerwenka, A. & Lanier, L.L. Natural killer cells, viruses and cancer. Nature Rev. Immunol. 1, 41–49 (2001).

    CAS  Article  Google Scholar 

  42. 42

    Perussia, B. Signaling for cytotoxicity. Nature Immunol. 1, 372–374 (2000).

    CAS  Article  Google Scholar 

  43. 43

    Bonnema, J.D., Karnitz, L.M., Schoon, R.A., Abraham, R.T. & Leibson, P.J. Fc receptor stimulation of phosphatidylinositol 3-kinase in natural killer cells is associated with protein kinase C-independent granule release and cell-mediated cytotoxicity. J. Exp. Med. 180, 1427–1435 (1994).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Jiang, K. Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells. Nature Immunol. 1, 419–425 (2000).

    CAS  Article  Google Scholar 

  45. 45

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    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  Article  PubMed  Google Scholar 

  47. 47

    Tangye, S.G. et al. Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. J. Immunol. 162, 6981–6985 (1999).

    CAS  PubMed  Google Scholar 

  48. 48

    Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Chuang, S.S., Kumaresan, P.R. & Mathew, P.A. 2B4 (CD244)-mediated activation of cytotoxicity and IFN-γ release in human NK cells involves distinct pathways. J. Immunol. 167, 6210–6216 (2001).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Latour, S. et al. Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nature Immunol. 2, 681–690 (2001).

    CAS  Article  Google Scholar 

  51. 51

    Mainiero, F. et al. RAC1/P38 MAPK signaling pathway controls β1 integrin-induced interleukin-8 production in human natural killer cells. Immunity 12, 7–16 (2000).

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Gismondi, A. et al. Cutting edge: functional role for proline-rich tyrosine kinase 2 in NK cell-mediated natural cytotoxicity. J. Immunol. 164, 2272–2276 (2000).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Helander, T.S. et al. ICAM-2 redistributed by ezrin as a target for killer cells. Nature 382, 265–268 (1996).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Biron, C.A., Nguyen, K.B., Pien, G.C., Cousens, L.P. & Salazar-Mather, T.P. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).

    CAS  Article  Google Scholar 

  55. 55

    Williams, N.S. et al. Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems. Immunol. Rev. 165, 47–61 (1998).

    CAS  Article  Google Scholar 

  56. 56

    Williams, N.S. et al. Differentiation of NK1. 1+, Ly49+ NK cells from flt3+ multipotent marrow progenitor cells. J. Immunol. 163, 2648–2656 (1999).

    CAS  Google Scholar 

  57. 57

    Roth, C., Carlyle, J.R., Takizawa, H. & Raulet, D.H. Clonal acquisition of inhibitory Ly49 receptors on developing NK cells is successively restricted and regulated by stromal class I MHC. Immunity 13, 143–153 (2000).

    CAS  Article  Google Scholar 

  58. 58

    Fischer, A. et al. Naturally occurring primary deficiencies of the immune system. Annu. Rev. Immunol. 15, 93–124 (1997).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    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  Article  Google Scholar 

  60. 60

    Cooper, M.A. et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 97, 3146–3151 (2001).

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Cooper, M.A., Fehniger, T.A. & Caligiuri, M.A. The biology of human natural killer-cell subsets. Trends Immunol. 22, 633–640 (2001).

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Tay, C.H. & Welsh, R.M. Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells. J. Virol. 71, 267–275 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Ashkar, A.A., Di Santo, J.P. & Croy, B.A. Interferon γ contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J. Exp. Med. 192, 259–270 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

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

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Rajagopalan, S., Fu, J. & Long, E.O. Cutting edge: induction of IFN-γ production but not cytotoxicity by the killer cell Ig-like receptor KIR2DL4 (CD158d) in resting NK cells. J. Immunol. 167, 1877–1881 (2001).

    CAS  Article  PubMed  Google Scholar 

  66. 66

    Yoder, J.A. et al. Immune-type receptor genes in zebrafish share genetic and functional properties with genes encoded by the mammalian leukocyte receptor cluster. Proc. Natl. Acad. Sci. USA. 98, 6771–6776 (2001).

    CAS  Article  PubMed  Google Scholar 

  67. 67

    Litman, G.W., Hawke, N.A. & Yoder, J.A. Novel immune-type receptor genes. Immunol. Rev. 181, 250–259 (2001).

    CAS  Article  PubMed  Google Scholar 

  68. 68

    Barten, R., Torkar, M., Haude, A., Trowsdale, J. & Wilson, M.J. Divergent and convergent evolution of NK-cell receptors. Trends Immunol. 22, 52–57 (2001).

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Hercend, T. & Schmidt, R.E. Characteristics and uses of natural killer cells. Immunol. Today 9, 291–293 (1988).

    CAS  Article  PubMed  Google Scholar 

  70. 70

    Kärre, K. MHC gene control of the natural killer system at the level of the target and the host. Semin. Cancer Biol. 2, 295–309 (1991).

    PubMed  Google Scholar 

  71. 71

    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  Article  Google Scholar 

  72. 72

    Kim, S., Iizuka, K., Aguila, H.L., Weissman, I.L. & Yokoyama, W.M. In vivo natural killer cell activity revealed by natural killer cell-deficient mice. Proc. Natl. Acad. Sci. USA. 97, 2731–2736 (2000).

    CAS  Article  PubMed  Google Scholar 

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We thank E. Colucci-Guyon, C. Vosshenrich, S. Zompi, A. Caraux and G. Litman for discussions, E. Schweighoffer, V. L. J. Tybulewicz, M. Turner, D. D. Billadeau and R. T. Abraham for collaborations; and C. E. Ford-Colucci for continuous support. Our apologies go to those authors whose work could not be cited due to space limitations.

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Correspondence to Francesco Colucci.

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Colucci, F., Di Santo, J. & Leibson, P. Natural killer cell activation in mice and men: different triggers for similar weapons?. Nat Immunol 3, 807–813 (2002).

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