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Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Author

Listed:
  • Priyanka Sathe

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Rebecca B. Delconte

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Fernando Souza-Fonseca-Guimaraes

    (QIMR Berghofer Medical Research Institute
    School of Medicine, University of Queensland)

  • Cyril Seillet

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Michael Chopin

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Cassandra J. Vandenberg

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Lucille C. Rankin

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Lisa A. Mielke

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ingela Vikstrom

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Tatiana B. Kolesnik

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Sandra E. Nicholson

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Eric Vivier

    (Centre d’Immunologie de Marseille-Luminy, INSERM)

  • Mark J. Smyth

    (QIMR Berghofer Medical Research Institute
    School of Medicine, University of Queensland)

  • Stephen L. Nutt

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Stefan P. Glaser

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Andreas Strasser

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Gabrielle T. Belz

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Sebastian Carotta

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Nicholas D. Huntington

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

Abstract

The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.

Suggested Citation

  • Priyanka Sathe & Rebecca B. Delconte & Fernando Souza-Fonseca-Guimaraes & Cyril Seillet & Michael Chopin & Cassandra J. Vandenberg & Lucille C. Rankin & Lisa A. Mielke & Ingela Vikstrom & Tatiana B. K, 2014. "Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5539
    DOI: 10.1038/ncomms5539
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    Cited by:

    1. Jun Dai & Shuyu Zheng & Matías M. Falco & Jie Bao & Johanna Eriksson & Sanna Pikkusaari & Sofia Forstén & Jing Jiang & Wenyu Wang & Luping Gao & Fernando Perez-Villatoro & Olli Dufva & Khalid Saeed & , 2024. "Tracing back primed resistance in cancer via sister cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Timothy R. McCulloch & Gustavo R. Rossi & Louisa Alim & Pui Yeng Lam & Joshua K. M. Wong & Elaina Coleborn & Snehlata Kumari & Colm Keane & Andrew J. Kueh & Marco J. Herold & Christoph Wilhelm & Percy, 2024. "Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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