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

Antoine Marçais (1) , Julien Cherfils-Vicini (2) , Charlotte Viant (3) , Sophie Degouve (1) , Sébastien Viel (1, 4) , Aurore Fenis (3) , Jessica Rabilloud (1) , Katia Mayol (1) , Armelle Tavares (1) , Jacques Bienvenu (4) , Yann-Gaël Gangloff (5) , Eric Gilson (2) , Eric Vivier (3) , Thierry Walzer (1)

1 Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases
2 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
3 CIML - Centre d'Immunologie de Marseille - Luminy
4 Service d'immunologie [Centre Hospitalier Lyon Sud - HCL]
5 LBMC UMR 5239 - Laboratoire de biologie et modélisation de la cellule

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: 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; Killer Cells; Knockout; Multiprotein Complexes; Inbred C57BL; Mice; Cells; Cultured; Herpesviridae Infections; Humans; Immunosuppressive Agents; Inflammation; Influenza A Virus; H1N1 Subtype; Interleukin-15; Muromegalovirus

Domaines: Immunologie; Bactériologie; Virologie

Antoine Marçais, Julien Cherfils-Vicini, Charlotte Viant, Sophie Degouve, Sébastien Viel, et al.. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nature Immunology, 2014, 15 (8), pp.749-757. ⟨10.1038/ni.2936⟩. ⟨hal-01911540⟩