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

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

Marçais A1,2,3,4,5, Cherfils-Vicini J#6, Viant C#7, Degouve S1,2,3,4,5, Viel S1,2,3,4,5,8, Fenis A7, Rabilloud J1,2,3,4,5, Mayol K1,2,3,4,5, Tavares A1,2,3,4,5, Bienvenu J8, Gangloff YG3,9, Gilson E6,10, Vivier E7, Walzer T1,2,3,4,5.

Author information

1
CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France.
2
Inserm, U1111, Lyon, France.
3
Ecole Normale Supérieure de Lyon, Lyon, France.
4
Université Lyon 1, Lyon, France.
5
CNRS, UMR5308, Lyon, France.
6
Institute for Research on Cancer and Aging, Nice (IRCAN), Nice University, CNRS UMR7284/INSERM U1081, Faculty of Medicine, Nice 06107, France.
7
Centre d'Immunologie de Marseille-Luminy, INSERM U1104; CNRS UMR7280; Aix Marseille Université, UM2, Marseille, France.
8
Laboratoire d'Immunologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, France.
9
LBMC; CNRS, UMR 5239, Lyon, France.
10
Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, BP 3079, 06202 Nice cedex 3, France.
#
Contributed equally

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.

PMID:
24973821
PMCID:
PMC4110708
DOI:
10.1038/ni.2936
[Indexed for MEDLINE]
Free PMC Article

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