Dok1 and Dok2 proteins regulate natural killer cell development and function

Authors

  • Javier Celis-Gutierrez,

    1. INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France
    2. Institut Paoli-Calmettes, Marseille, France
    3. CNRS, UMR7258, Centre de Recherche en Cancérologie de Marseille, Marseille, France
    4. Aix-Marseille Université, Marseille, France
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  • Marilyn Boyron,

    1. Aix-Marseille Université, Marseille, France
    2. Centre d'Immunologie de Marseille-Luminy, INSERM U1104, Marseille, France
    3. CNRS, UMR7280, Marseille, France
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    • These authors contributed equally to this work
  • Thierry Walzer,

    1. Aix-Marseille Université, Marseille, France
    2. Centre d'Immunologie de Marseille-Luminy, INSERM U1104, Marseille, France
    3. CNRS, UMR7280, Marseille, France
    4. Université de Lyon, INSERM U1111, Lyon, France
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    • These authors contributed equally to this work
  • Pier Paolo Pandolfi,

    1. Departments of Medicine and Pathology, Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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  • Stipan Jonjić,

    1. Department for Histology and Embryology, School of Medicine, University of Rijeka, Rijeka, Croatia
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  • Daniel Olive,

    1. INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France
    2. Institut Paoli-Calmettes, Marseille, France
    3. CNRS, UMR7258, Centre de Recherche en Cancérologie de Marseille, Marseille, France
    4. Aix-Marseille Université, Marseille, France
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  • Marc Dalod,

    1. Aix-Marseille Université, Marseille, France
    2. Centre d'Immunologie de Marseille-Luminy, INSERM U1104, Marseille, France
    3. CNRS, UMR7280, Marseille, France
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  • Eric Vivier,

    1. Aix-Marseille Université, Marseille, France
    2. Centre d'Immunologie de Marseille-Luminy, INSERM U1104, Marseille, France
    3. CNRS, UMR7280, Marseille, France
    4. Service d'Immunologie, Assistance Publique – Hôpitaux de Marseille, Hôpital de la Conception, Marseille, France
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  • Jacques A Nunès

    Corresponding author
    1. INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France
    2. Institut Paoli-Calmettes, Marseille, France
    3. CNRS, UMR7258, Centre de Recherche en Cancérologie de Marseille, Marseille, France
    4. Aix-Marseille Université, Marseille, France
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Abstract

Natural killer (NK) cells are involved in immune responses against tumors and microbes. NK-cell activation is regulated by intrinsic and extrinsic mechanisms that ensure NK tolerance and efficacy. Here, we show that the cytoplasmic signaling molecules Dok1 and Dok2 are tyrosine phosphorylated upon NK-cell activation. Overexpression of Dok proteins in human NK cells reduces cell activation induced by NK-cell-activating receptors. Dok1 and Dok2 gene ablation in mice induces an NK-cell maturation defect and leads to increased IFN-γ production induced by activating receptors. Taken together, these results reveal that Dok1 and Dok2 proteins are involved in an intrinsic negative feedback loop downstream of NK-cell-activating receptors in mouse and human.

Synopsis

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Dok1 and Dok2 proteins are expressed in NK cells and regulate NK-cell signaling

  • Dok proteins are tyrosine phosphorylated upon engagement of NK-cell-activating receptors.
  • Dok1 and Dok2 negatively regulate NK-cell activation induced by engagement of activating receptors.
  • Combined deficiency in Dok1 and Dok2 impairs NK-cell development in vivo.

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