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

• Published in: Nature Immunology 2007-08, Vol.8 (8), p.856-863
• Main Authors: Puthalakath, Hamsa, Smyth, Mark J, Motoyama, Noboru, Strasser, Andreas, Huang, David C S, Dewson, Grant, Tarlinton, David M, Willis, Simon N, Tabarias, Hyacinth, Huntington, Nicholas D, Degli-Esposti, Mariapia A, Michalak, Ewa M, Nutt, Stephen L, Gunn, Priscilla, Naik, Edwina
• Format: Article
• Language: English
• Subjects: Animals; Antigen receptors, T cell; Apoptosis; Apoptosis - immunology; Apoptosis Regulatory Proteins - immunology; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Biomedical and Life Sciences; Biomedicine; Cell Survival - immunology; Flow Cytometry; Forkhead Box Protein O3; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Immunoblotting; Immunology; Inactivation; Infectious Diseases; Interleukin-15; Interleukin-15 - immunology; Interleukin-15 - metabolism; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mitogen-Activated Protein Kinase 3 - immunology; Mitogen-Activated Protein Kinase 3 - metabolism; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - immunology; Neoplasm Proteins - metabolism; Phosphatidylinositol 3-Kinases - immunology; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; Polymerase Chain Reaction; Proto-Oncogene Proteins - immunology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - immunology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors; Survival; T cells
• ISSN: 1529-2908; 1529-2916; 1365-2567
• DOI: 10.1038/ni1487

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.