Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Michael T. McCarthy
  • Christopher A. O’CallaghanEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_568


Historical Background

Natural killer (NK) cells are key components of the innate immune response and can mediate cellular cytotoxicity without previous antigen exposure. The mechanisms underlying NK cell activation have been uncovered in a stepwise fashion from the early 1980s (for a detailed review of the field and its development see (Lanier 2008)). The role of the CD16 FcγRIII cell surface receptor in antibody-dependent NK cell activation was described in 1983. In 1986, Karre and colleagues proposed the “missing self-hypothesis” hypothesis and demonstrated the presence of inhibitory NK cell surface receptors responsive to the self-MHC (major histocompatibility complex) molecules on normal host cells. The search for antibody-independent NK cell activating receptors led to the identification of the NKG2 family of NK cell receptors in 1991. Among these was NKG2D, a molecule that shared limited homology...

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  1. Bahram S, Bresnahan M, Geraghty D, Spies T. A second lineage of mammalian major histocompatibility complex class I genes. Proc Natl Acad Sci U S A. 1994;91(14):6259.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Bauer S, Groh V, Steinle A, Phillips JH, Lanier LL, Spies T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999;285(5428):727–9.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Belting L, Hömberg N, Przewoznik M, Brenner C, Riedel T, Flatley A, et al. Critical role of the NKG2D receptor for NK cell-mediated control and immune escape of B-cell lymphoma. Eur J Immunol. 2015;45(9):2593–601.CrossRefPubMedGoogle Scholar
  4. Ehrlich LIR, Ogasawara K, Hamerman JA, Takaki R, Zingoni A, Allison JP, et al. Engagement of NKG2D by cognate ligand or antibody alone is insufficient to mediate costimulation of human and mouse CD8+ T cells. J Immunol. 2005;174(4):1922–31.CrossRefPubMedGoogle Scholar
  5. Fauriat C, Long E, Ljunggren H, Bryceson Y. Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood. 2010;115(11):2167.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Guerra N, Tan Y, Joncker N, Choy A, Gallardo F, Xiong N, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008;28(4):571–80.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Hedlund M, Stenqvist A-C, Nagaeva O, Kjellberg L, Wulff M, Baranov V, et al. Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function. J Immunol. 2009;183(1):340–51.CrossRefPubMedGoogle Scholar
  8. Lanier L. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008;9(5):495–502.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Lanier LL. NKG2D receptor and its ligands in host defense. Cancer Immunol Res. 2015;3(6):575–82.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nat Immunol. 2001;2(5):443–51.CrossRefPubMedGoogle Scholar
  11. Maasho K, Opoku-Anane J, Marusina AI, Coligan JE, Borrego F. NKG2D is a costimulatory receptor for human naive CD8+ T cells. J Immunol. 2005;174(8):4480–4.CrossRefPubMedGoogle Scholar
  12. McQueen B, Trace K, Whitman E, Bedsworth T, Barber A. Natural killer group 2D and CD28 receptors differentially activate mammalian/mechanistic target of rapamycin to alter murine effector CD8+ T-cell differentiation. Immunology. 2016;147(3):305–20.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Mistry AR, O’Callaghan CA. Regulation of ligands for the activating receptor NKG2D. Immunology. 2007;121(4):439–47.PubMedPubMedCentralCrossRefGoogle Scholar
  14. O’Callaghan C. NKG2D. AfCS-Nature Molecule Pages. 2009. http://www.signaling-gateway.org/molecule/query?afcsid=A001666&mpv=1. Accessed 2 Jul 2016.
  15. O’Callaghan C, Cerwenka A, Willcox B, Lanier L, Bjorkman P. Molecular competition for NKG2D: H60 and RAE1 compete unequally for NKG2D with dominance of H60. Immunity. 2001;15(2):201–11.CrossRefPubMedGoogle Scholar
  16. Quatrini L, Molfetta R, Zitti B, Peruzzi G, Fionda C, Capuano C, et al. Ubiquitin-dependent endocytosis of NKG2D-DAP10 receptor complexes activates signaling and functions in human NK cells. Sci Signal. 2015;8(400):ra108–8.CrossRefGoogle Scholar
  17. Rajasekaran K, Xiong V, Fong L, Gorski J, Malarkannan S. Functional dichotomy between NKG2D and CD28-mediated co-stimulation in human CD8+ t cells. PLoS One. 2010;5(9):1–10.CrossRefGoogle Scholar
  18. Wolan DW, Teyton L, Rudolph MG, Villmow B, Bauer S, Busch DH, et al. Crystal structure of the murine NK cell-activating receptor NKG2D at 1.95 Å. Nat Immunol. 2001;2(3):248–54.CrossRefPubMedGoogle Scholar
  19. Zafirova B, Mandarić S, Antulov R, Krmpotić A, Jonsson H, Yokoyama WM, et al. Altered NK cell development and enhanced NK cell-mediated resistance to mouse cytomegalovirus in NKG2D-deficient mice. Immunity. 2009;31(2):270–82.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Zhu S, Phatarpekar PV, Denman CJ, Senyukov VV, Somanchi SS, Nguyen-Jackson HT, et al. Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation. Blood Am Soc Hematol. 2014;124(3):403–11.Google Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  • Michael T. McCarthy
    • 1
  • Christopher A. O’Callaghan
    • 1
    Email author
  1. 1.Centre for Cellular and Molecular Physiology, Nuffield Department of Clinical MedicineUniversity of OxfordHeadington, OxfordUK