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

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

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171 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)856-863
Number of pages8
JournalNature Immunology
Volume8
Issue number8
DOIs
Publication statusPublished - 1 Aug 2007
Externally publishedYes

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