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

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.

authors

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

publication date

  • August 2007

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