The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells

Nat Immunol. 2014 Aug;15(8):749-757. doi: 10.1038/ni.2936. Epub 2014 Jun 29.

Abstract

Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK) cells. The molecular basis for this duality of action remains unknown. Here we found that the metabolic checkpoint kinase mTOR was activated and boosted bioenergetic metabolism after exposure of NK cells to high concentrations of IL-15, whereas low doses of IL-15 triggered only phosphorylation of the transcription factor STAT5. mTOR stimulated the growth and nutrient uptake of NK cells and positively fed back on the receptor for IL-15. This process was essential for sustaining NK cell proliferation during development and the acquisition of cytolytic potential during inflammation or viral infection. The mTORC1 inhibitor rapamycin inhibited NK cell cytotoxicity both in mice and humans; this probably contributes to the immunosuppressive activity of this drug in different clinical settings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Herpesviridae Infections / immunology
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Inflammation / immunology
  • Influenza A Virus, H1N1 Subtype / immunology
  • Interleukin-15 / immunology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation / immunology*
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / immunology
  • Muromegalovirus / immunology
  • Orthomyxoviridae Infections / immunology
  • Poly I-C / immunology
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / immunology
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / immunology*

Substances

  • Immunosuppressive Agents
  • Interleukin-15
  • Multiprotein Complexes
  • STAT5 Transcription Factor
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Poly I-C
  • Sirolimus