title: The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells.
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.
authors: CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors: Antoine
authors: A
authors: Marçais
authors: Institute for Research on Cancer and Aging, Nice (IRCAN), Nice University, CNRS UMR7284/INSERM U1081, Faculty of Medicine, Nice 06107, France.
authors: Julien
authors: J
authors: Cherfils-Vicini
authors: Centre d'Immunologie de Marseille-Luminy, INSERM U1104; CNRS UMR7280; Aix Marseille Université, UM2, Marseille, France.
authors: Charlotte
authors: C
authors: Viant
authors: CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors: Sophie
authors: S
authors: Degouve
authors: CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Lyon, France.|CNRS, UMR5308, Lyon, France.|Laboratoire d'Immunologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, France.
authors: Sébastien
authors: S
authors: Viel
authors: Centre d'Immunologie de Marseille-Luminy, INSERM U1104; CNRS UMR7280; Aix Marseille Université, UM2, Marseille, France.
authors: Aurore
authors: A
authors: Fenis
authors: CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors: Jessica
authors: J
authors: Rabilloud
authors: CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors: Katia
authors: K
authors: Mayol
authors: CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors: Armelle
authors: A
authors: Tavares
authors: Laboratoire d'Immunologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, France.
authors: Jacques
authors: J
authors: Bienvenu
authors: Ecole Normale Supérieure de Lyon, Lyon, France.|LBMC; CNRS, UMR 5239, Lyon, France.
authors: Yann-Gaël
authors: YG
authors: Gangloff
authors: Institute for Research on Cancer and Aging, Nice (IRCAN), Nice University, CNRS UMR7284/INSERM U1081, Faculty of Medicine, Nice 06107, France.|Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, BP 3079, 06202 Nice cedex 3, France.
authors: Eric
authors: E
authors: Gilson
authors: Centre d'Immunologie de Marseille-Luminy, INSERM U1104; CNRS UMR7280; Aix Marseille Université, UM2, Marseille, France.
authors: Eric
authors: E
authors: Vivier
authors: CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors: Thierry
authors: T
authors: Walzer
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006566:Herpesviridae Infections / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D018146:Muromegalovirus / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology; D011070:Poly I-C / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D019409:Interleukin-15; D046912:Multiprotein Complexes; D050799:STAT5 Transcription Factor; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D011070:Poly I-C; D020123:Sirolimus