The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells
Résumé
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.
Mots clés
Killer Cells
Knockout
Multiprotein Complexes
Inbred C57BL
Mice
Cells
Cultured
Herpesviridae Infections
Humans
Immunosuppressive Agents
Inflammation
Influenza A Virus
H1N1 Subtype
Interleukin-15
Muromegalovirus
Orthomyxoviridae Infections
Poly I-C
Signal Transduction
Sirolimus
STAT5 Transcription Factor
TOR Serine-Threonine Kinases
Animals
Cell Proliferation
Mechanistic Target of Rapamycin Complex 2
Mechanistic Target of Rapamycin Complex 1
Lymphocyte Activation
Natural
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