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NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway

Abstract

The effector functions of natural killer cells are regulated by activating receptors, which recognize stress-inducible ligands expressed on target cells and signal through association with signaling adaptors. Here we developed a mouse model in which a fusion of the signaling adaptor DAP10 and ubiquitin efficiently downregulated expression of the activating receptor NKG2D on the surfaces of natural killer cells. With this system, we identified coupling of the signaling pathways triggered by NKG2D and DAP10 to those initiated by the interleukin 15 receptor. We suggest that this coupling of activating receptors to other receptor systems could function more generally to regulate cell type–specific signaling events in distinct physiological contexts.

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Figure 1: Cell surface expression of the NKG2D-DAP10 receptor complex is downregulated by DAP10-U6.
Figure 2: Lower NKG2D-dependent cytotoxicity and IFN-γ production in transgenic cells.
Figure 3: IL-15 unresponsiveness of transgenic NK cells.
Figure 4: Impaired STAT5 phosphorylation in transgenic NK cells.
Figure 5: Priming of DAP10 signaling by IL-15-activated Jak3.

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Acknowledgements

We thank D. Raulet (University of California, Berkeley) for DAP10-specific antiserum and communication of unpublished results; W. Yokoyama for the KY-1 cells; S. Holley and C. Anicelli for help with mouse work; G. Tokmoulina and T. Taylor for assistance with cell sorting; and S. Shih and members of the lab for discussions and for critically reviewing the manuscript. VACD2 vector was provided by D. Kioussis (National Institute for Medical Research, London, UK), and wild-type and catalytically inactive Jak3 were from J. Ihle (St. Jude Children's Research Hospital). Supported by the Howard Hughes Medical Institute and the National Institutes of Health (AI-0466888 and AI-055502).

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Correspondence to Tiffany Horng or Ruslan Medzhitov.

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Supplementary Figures 1–10, Table 1 and Methods (PDF 1347 kb)

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Horng, T., Bezbradica, J. & Medzhitov, R. NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway. Nat Immunol 8, 1345–1352 (2007). https://doi.org/10.1038/ni1524

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