Journal Article

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

Strasser, Andreas, Gunn, Priscilla, Dewson, Grant, Tarlinton, David M, Smyth, Mark J, Puthalakath, Hamsa, Huntington, Nicholas D, Willis, Simon N, Nutt, Stephen L, Tabarias, Hyacinth, Degli-Esposti, Mariapia A, Naik, Edwina, Motoyama, Noboru, Michalak, Ewa M, Huang, David C S

2007

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 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