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NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases

Abstract

In activated mouse natural killer (NK) cells, the NKG2D receptor associates with two intracellular adaptors, DAP10 and DAP12, which trigger phosphatidyl inositol 3 kinase (PI3K) and Syk family protein tyrosine kinases, respectively. Here we show that cytotoxicity, but not cytokine production, is triggered by NKG2D in activated NK cells lacking either DAP12 or the Syk family members Syk and ZAP70. Inhibition of PI3K blocks this cytotoxicity, suggesting that the DAP10-PI3K pathway is sufficient to initiate NKG2D-mediated killing of target cells. Our results highlight signaling divergence in the effector functions of NKG2D and indicate that alternative associations between a receptor and its adaptors may provide a single receptor with a dual 'on-switch', giving mouse NK cells more choices through which to trigger cytotoxicity.

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Figure 1: Normal NKG2D expression in the absence of Syk and ZAP70.
Figure 2: NKG2D-initiated cytotoxicity in activated NK cells.
Figure 3: A PI3K specific inhibitor blocks NKG2D-initiated cytotoxicity.
Figure 4: NKG2D enhances cytotoxicity independently of DAP12 and Syk-ZAP70.
Figure 5: In vivo rejection of tumor cells expressing NKG2D ligands.
Figure 6: NKG2D-initiated cytotoxicity in resting NK cells.
Figure 7: Time course of killing activity against target cells expressing NKG2D ligands.
Figure 8: The DAP12-Syk-ZAP70 pathway is essential for NKG2D-mediated IFN-γ production.

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Acknowledgements

We thank A. Weiss and T. Kadlecek for Zap70−/− mice; E. Corcuff, O. Richard and T. Chen for help; A. Caraux for reading the manuscript; and P. Leibson and D. Billadeau for discussions and for sharing unpublished data. This work was supported by grants from the Pasteur Institute, Ligue Nationale Contre le Cancer, Association pour la Recherche sur le Cancer, Institut National de la Santé et de la Recherche Medicale (to F.C. and J.P.D.) and the Medical Research Council (to V.J.L.T.), and grant R01 CA89294 from the National Institutes of Health (to L.L.L.). S.Z. is supported by a grant from Ligue Nationale Contre le Cancer; J.A.H. is supported by a grant from Irvington Institute for Immunological Research; K.O. is supported by Human Frontier Science Program Long-term Fellowship; E.S. is supported by the European Molecular Biology Organization; and L.L.L. is a Research Professor of the American Cancer Society.

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Correspondence to Francesco Colucci.

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Zompi, S., Hamerman, J., Ogasawara, K. et al. NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases. Nat Immunol 4, 565–572 (2003). https://doi.org/10.1038/ni930

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