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NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation


NKG2D is a receptor on natural killer (NK) cells and cytotoxic T lymphocytes that binds major histocompatibility complex (MHC) class I–like ligands expressed primarily on virally infected and neoplastic cells. In vitro studies indicate that NKG2D provides costimulation through an associated adapter, DAP10, which recruits phosphatidylinositol-3 kinase. Here we show that in DAP10-deficient mice, CD8+ T cells lack NKG2D expression and are incapable of mounting tumor-specific responses. However, DAP10-deficient NK cells express a functional NKG2D receptor due to the association of NKG2D with another adapter molecule, DAP12 (also known as KARAP), which recruits protein tyrosine kinases. Thus, NKG2D is a versatile receptor that, depending on the availability of adapter partners, mediates costimulation in T cells and/or activation in NK cells.

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Figure 1: Generation of DAP10−/− mice.
Figure 2: Expression of NKG2D in DAP10−/− and wild-type mice.
Figure 3: Expression of NKG2D on activated T and NK cells from DAP10−/− and control mice.
Figure 4: Association of NKG2D with DAP10 and DAP12 in NK cells.
Figure 5: NKG2D-mediated cytotoxic activity of resting and IL-2–cultured NK cells from DAP10+/+ and DAP10−/− mice.
Figure 6: Tumor-specific CTL responses in DAP10+/+ and DAP10−/− mice.
Figure 7: Comparison of NKG2D+ CD8+ T cell frequency in spleens and RMAS.Rae-1γ tumors.


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

    Article  CAS  Google Scholar 

  2. Bauer, S. et al. Activation of NK cells and T cells by NKG2D, a receptor for stress- inducible MICA. Science 285, 727–729 (1999).

    Article  CAS  Google Scholar 

  3. Cerwenka, A. et al. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12, 721–727 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Cosman, D. et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133 (2001).

    Article  CAS  Google Scholar 

  6. Sutherland, C.L. et al. UL16-binding proteins, novel MHC class I-related Proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells. J. Immunol. 168, 671–679 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Groh, V., Steinle, A., Bauer, S. & Spies, T. Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 279, 1737–1740 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Cerwenka, A., Baron, J.L. & Lanier, L.L. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc. Natl. Acad. Sci. USA 98, 11521–11526 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Lanier, L.L. & Bakker, A.B. The ITAM-bearing transmembrane adaptor DAP12 in lymphoid and myeloid cell function. Immunol. Today 21, 611–614 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. McVicar, D.W. et al. DAP12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase. J. Biol. Chem. 273, 32934–32942 (1998).

    Article  CAS  Google Scholar 

  17. Tomasello, E., Blery, M., Vely, E. & Vivier, E. Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells. Semin. Immunol. 12, 139–147 (2000).

    Article  CAS  Google Scholar 

  18. Chang, C. et al. Cutting edge: KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties. J. Immunol. 163, 4651–4654 (1999).

    CAS  PubMed  Google Scholar 

  19. Wu, J., Cherwinski, H., Spies, T., Phillips, J.H. & Lanier, L.L. DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells. J. Exp. Med. 192, 1059–1068 (2000).

    Article  CAS  Google Scholar 

  20. Pages, F. et al. Binding of phosphatidylinositol-3-OH kinase to CD28 is required for T-cell signalling. Nature 369, 327–329 (1994).

    Article  CAS  Google Scholar 

  21. Prasad, K.V. et al. T-cell antigen CD28 interacts with the lipid kinase phosphatidylinositol 3-kinase by a cytoplasmic Tyr(P)-Met-Xaa-Met motif. Proc. Natl. Acad. Sci. USA 91, 2834–2838 (1994).

    Article  CAS  Google Scholar 

  22. Schwenk, F., Baron, U. & Rajewsky, K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. Idris, A.H. et al. The natural killer gene complex genetic locus Chok encodes Ly-49D, a target recognition receptor that activates natural killing. Proc. Natl. Acad. Sci. USA 96, 6330–6335 (1999).

    Article  CAS  Google Scholar 

  26. Wolpert, E.Z. et al. Generation of CD8+ T cells specific for transporter associated with antigen processing deficient cells. Proc. Natl. Acad. Sci. USA 94, 11496–11501 (1997).

    Article  CAS  Google Scholar 

  27. Kelly, J.M., Takeda, K., Darcy, P.K., Yagita, H. & Smyth, M.J. A role for IFN-γ in primary and secondary immunity generated by NK cell-sensitive tumor-expressing CD80 in vivo. J. Immunol. 168, 4472–4479 (2002).

    Article  CAS  Google Scholar 

  28. Kelly, J.M. et al. Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. Nature Immunol. 3, 83–90 (2002).

    Article  CAS  Google Scholar 

  29. Roberts, A.I. et al. NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J. Immunol. 167, 5527–5530 (2001).

    Article  CAS  Google Scholar 

  30. Diefenbach, A. et al. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nature Immunol.; published online 11 November 2002 (doi:10.1038/ni858).

  31. Long, E.O. Tumor cell recognition by natural killer cells. Semin. Cancer Biol. 12, 57–61 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  33. Riegert, P. & Gilfillan, S. A conserved sequence block in the murine and human TCR Jα region: assessment of regulatory function in vivo. J. Immunol. 162, 3471–3480 (1999).

    CAS  PubMed  Google Scholar 

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We thank K. Rajewsky for the Cre-transgenic mice, T. Miyazaki for the original vial of E14.1 cells, S. Kuschert for blastocyst injection, E. Wagner and colleagues for animal care at the former Basel Institute for Immunology and C. Strader for technical assistance. E. L. H. was supported by a training grant from the Cancer Research Institute and W. M. Y. was supported by NIH grants, the Barnes-Jewish Hospital Foundation and the Howard Hughes Medical Institute.

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Correspondence to Marco Colonna.

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Gilfillan, S., Ho, E., Cella, M. et al. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nat Immunol 3, 1150–1155 (2002).

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