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Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells

Nature Immunology volume 10, pages 973–980 (2009)Cite this article

Abstract

The adaptors SAP, EAT-2 and ERT are specific to cells of the immune system and belong to the SAP family. All three are expressed in natural killer (NK) cells. Here we examined the global function of the SAP family using mice lacking SAP, EAT-2 and ERT. These adaptors acted together in a mechanism that was essential for the elimination of hematopoietic but not nonhematopoietic cells by NK cells. This function was mediated by many receptors of the SLAM family on NK cells that were engaged by ligands found solely on hematopoietic cells. In the absence of SAP-related adaptors, SLAM receptors lost their activating function and became inhibitory receptors that repressed other activating receptors, such as NKG2D. Hence, the SAP family is essential for the elimination of unwanted hematopoietic cells by NK cells.

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Figure 1: Normal NK cell development in the absence of the SAP family.
Figure 2: Defective natural cytotoxicity by NK cells lacking SAP family adaptors in response to hematopoietic target cells.
Figure 3: Defective IFN-γ production and CD107a induction in NK cells lacking SAP family adaptors in response to hematopoietic target cells.
Figure 4: Compromised in vivo clearance of abnormal hematopoietic cells in mice lacking SAP family adaptors.
Figure 5: Activation of NK cells by hematopoietic cells involves multiple SLAM family receptors.
Figure 6: SLAM family receptors are converted into inhibitory receptors in NK cells lacking SAP family adaptors.
Figure 7: Effect of deficiency of various SAP family adaptors on natural cytotoxicity against B16 derivatives expressing SLAM family receptor ligands.
Figure 8: Mechanism of inhibition by SLAM family receptors in the absence of the SAP family.

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Acknowledgements

We thank D. Davidson for critical reading of the manuscript. Supported by the Canadian Institutes of Health Research (Veillette laboratory and Z.D.), the Canadian Cancer Society Research Institute (Veillette laboratory and M.-E.C.-M.), the Howard Hughes Medical Institute (Veillette laboratory and A.V.), the Institut National de la Santé et de la Recherche Médicale (Latour laboratory), the Agence Nationale de la Recherche (Latour laboratory), the Ligue Nationale Contre le Cancer–Ile de France (Latour laboratory), the Clinical Research Institute of Montreal (Z.D.), the Centre National de la Recherche Scientifique (S.L.) and Canada Research Chair Program (A.V.).

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada

    Zhongjun Dong, Mario-Ernesto Cruz-Munoz, Ming-Chao Zhong, Riyan Chen & André Veillette

  2. Unité Institut National de la Santé et de la Recherche Médicale 768, Hôpital Necker Enfants-Malades, Paris, France

    Sylvain Latour

  3. Department of Medicine, University of Montréal, Montréal, Québec, Canada

    André Veillette

  4. Department of Medicine, McGill University, Montréal, Québec, Canada

    André Veillette

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  1. Zhongjun Dong
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Z.D. conceived of the research, did experiments, analyzed data and wrote the manuscript; M.-E.C.-M., R.C. and M.-C.Z. conceived of the research and generated critical reagents; S.L. did research, analyzed data and generated critical reagents; and A.V. conceived of the research, generated reagents, analyzed data and wrote the manuscript.

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Correspondence to André Veillette.

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Dong, Z., Cruz-Munoz, ME., Zhong, MC. et al. Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells. Nat Immunol 10, 973–980 (2009). https://doi.org/10.1038/ni.1763

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