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Interleukin 15–mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1

Abstract

Interleukin 15 (IL-15) promotes the survival of natural killer (NK) cells by preventing apoptosis through mechanisms unknown at present. Here we identify Bim, Noxa and Mcl-1 as key regulators of IL-15-dependent survival of NK cells. IL-15 suppressed apoptosis by limiting Bim expression through the kinases Erk1 and Erk2 and mechanisms dependent on the transcription factor Foxo3a, while promoting expression of Mcl-1, which was necessary and sufficient for the survival of NK cells. Withdrawal of IL-15 led to upregulation of Bim and, accordingly, both Bim-deficient and Foxo3a−/− NK cells were resistant to cytokine deprivation. Finally, IL-15-mediated inactivation of Foxo3a and cell survival were dependent on phosphotidylinositol-3-OH kinase. Thus, IL-15 regulates the survival of NK cells at multiple steps, with Bim and Noxa being key antagonists of Mcl-1, the critical survivor factor in this process.

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Figure 1: IL-15 deprivation causes accumulation of Bim in NK cells.
Figure 2: Bim is not essential for development or function of NK cells.
Figure 3: Apoptosis-resistant NK cells accumulate in Bim−/− mice.
Figure 4: PI(3)K is essential for IL-15-mediated survival of NK cells.
Figure 5: IL-15 suppresses Foxo3a-mediated Bim upregulation.
Figure 6: IL-15-induced upregulation of Mcl-1 promotes the survival of NK cells.
Figure 7: Noxa acts together with Bim in mediating NK cell apoptosis.

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Acknowledgements

We thank C. Scott, L. Lee, Y. Hayakawa, J. Brady, C. Vandenberg and the support staff of the Walter and Eliza Hall Institute of Medical Research for technical assistance and reagents; P. Bouillet, J. Adams and S. Cory (Walter and Eliza Hall Institute) and B. Vanhaesenbroek (Babraham Institute) for gene-targeted mice; R. Anderson (The Peter MacCallum Cancer Centre) for mouse monoclonal anti-Hsp70; and Abbot Laboratories for ABT-737. Supported by the Cancer Council Victoria (N.D.H. and S.N.W.), the National Health and Medical Research Council of Australia (257502, 251608 and 356202), the National Cancer Institute (US; CA 80188 and CA 43540), the Leukemia and Lymphoma Society of America (SCOR 7015), and the Juvenile Diabetes Research Foundation–National Health and Medical Research Council and the Walter and Eliza Hall of Medical Research Metcalf Fellowship (S.L.N.).

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N.D.H. did experiments, analyzed data and wrote the manuscript; H.P., P.G., E.N., H.T., G.D. and S.N.W. did experiments; E.M.M. and N.M. provided unpublished genetically modified mice; M.A.D.-E., D.C.S.H. and M.J.S. designed research; and S.L.N., D.M.T. and A.S. designed research, analyzed data and wrote the manuscript.

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Correspondence to Nicholas D Huntington or Andreas Strasser.

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Huntington, N., Puthalakath, H., Gunn, P. et al. Interleukin 15–mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat Immunol 8, 856–863 (2007). https://doi.org/10.1038/ni1487

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