Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Nat Commun. 2014 Aug 14;5:4539. doi: 10.1038/ncomms5539.

Abstract

The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3'-UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cytokines / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Gene Deletion*
  • Immune System Diseases / genetics*
  • Immune System Diseases / physiopathology
  • Immunity, Innate / genetics*
  • Immunity, Innate / physiology
  • Interleukin-15 / pharmacology
  • Interleukin-15 / physiology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / metabolism*
  • Killer Cells, Natural / pathology*
  • Lymphopenia / genetics
  • Lymphopenia / pathology
  • Lymphopenia / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • STAT5 Transcription Factor / physiology
  • Signal Transduction / physiology

Substances

  • Cytokines
  • Interleukin-15
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • STAT5 Transcription Factor