Journal article

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

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 Kolesnik, Sandra E Nicholson, Eric Vivier, Mark J Smyth, Stephen L Nutt, Stefan P Glaser, Andreas Strasser, Gabrielle T Belz, Sebastian Carotta, Nicholas D Huntington

Nature Communications | NATURE PUBLISHING GROUP | Published : 2014

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 mela..

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Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by National Health and Medical Research Council of Australia, Dora Lush Training Scholarship


Awarded by Australia Fellowship


Awarded by Leukemia and Lymphoma Society (SCOR)


Awarded by Cancer Council Victoria


Funding Acknowledgements

We wish to thank Philippe Bouillet, Suzanne Cory and Lothar Hennighausen for their generous gift of mice and reagents and Tania Camilleri, Pradnya Gangatirkar, Hesham Abdulla, Victor Peperzak, Cathy Quillici, Mary Camilleri and Anndrea Pomphrey for assistance. We thank the staff of the WEHI Animal Services, the flow cytometry facility and Clinical Translational Centre. This work is supported by programme and project grants from the National Health and Medical Research Council of Australia (1027472 to S. C., N.D.H. and G. T. B., 1047903 to GTB and LAM, 1046010 and 1016701 to AS, 487922 to SEN and 1049407 to NDH). This work is supported by fellowships from the National Health and Medical Research Council of Australia (GNT0461276 to NDH, 1020363 to AS, Dora Lush Training Scholarship to LCR), the Australian Research Council (SC, GTB, SLN), Australia Fellowship (628623) to MJS, Cancer Australia (LAM), the Leukemia and Lymphoma Society (SCOR grant no. 7413) to AS, the Cancer Council Victoria (1052309) to AS and The Menzies Foundation (NDH). EV's laboratory is supported by the European Research Council (THINK Advanced Grant) and by institutional grants from INSERM, CNRS and Aix Marseille to CIML. EV is a scholar of the Institut Universitaire de France. This study was made possible through the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme.