title: TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway.
abstract: Transforming growth factor-β (TGF-β) is a major immunosuppressive cytokine that maintains immune homeostasis and prevents autoimmunity through its antiproliferative and anti-inflammatory properties in various immune cell types. We provide genetic, pharmacologic, and biochemical evidence that a critical target of TGF-β signaling in mouse and human natural killer (NK) cells is the serine and threonine kinase mTOR (mammalian target of rapamycin). Treatment of mouse or human NK cells with TGF-β in vitro blocked interleukin-15 (IL-15)-induced activation of mTOR. TGF-β and the mTOR inhibitor rapamycin both reduced the metabolic activity and proliferation of NK cells and reduced the abundances of various NK cell receptors and the cytotoxic activity of NK cells. In vivo, constitutive TGF-β signaling or depletion of mTOR arrested NK cell development, whereas deletion of the TGF-β receptor subunit TGF-βRII enhanced mTOR activity and the cytotoxic activity of the NK cells in response to IL-15. Suppression of TGF-β signaling in NK cells did not affect either NK cell development or homeostasis; however, it enhanced the ability of NK cells to limit metastases in two different tumor models in mice. Together, these results suggest that the kinase mTOR is a crucial signaling integrator of pro- and anti-inflammatory cytokines in NK cells. Moreover, we propose that boosting the metabolic activity of antitumor lymphocytes could be an effective strategy to promote immune-mediated tumor suppression.
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France. Laboratoire d'Immunologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite 69310, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Viel
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Marçais
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. School of Medicine, The University of Queensland, Herston, Queensland 4006, Australia.
authors.forename: Fernando Souza-Fonseca
authors.initials: FS
authors.lastname: Guimaraes
authors.affiliation: School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Roisin
authors.initials: R
authors.lastname: Loftus
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Rabilloud
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France.
authors.forename: Morgan
authors.initials: M
authors.lastname: Grau
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Degouve
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France.
authors.forename: Sophia
authors.initials: S
authors.lastname: Djebali
authors.affiliation: Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.
authors.forename: Amélien
authors.initials: A
authors.lastname: Sanlaville
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France. Laboratoire d'Immunologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite 69310, France.
authors.forename: Emily
authors.initials: E
authors.lastname: Charrier
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France. Laboratoire d'Immunologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite 69310, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bienvenu
authors.affiliation: Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France. TGF-beta and immunoregulation group, DKFZ, Heidelberg 69121, Germany.
authors.forename: Julien C
authors.initials: JC
authors.lastname: Marie
authors.affiliation: Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marvel
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: Liam
authors.initials: L
authors.lastname: Town
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
authors.affiliation: Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bartholin
authors.affiliation: School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Finlay
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. School of Medicine, The University of Queensland, Herston, Queensland 4006, Australia. mark.smyth@qimrberghofer.edu.au thierry.walzer@inserm.fr.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Centre International de Recherche en Infectiologie (CIRI), 69007 Lyon, France. INSERM U1111, 69007 Lyon, France. Ecole Normale Supérieure de Lyon, 69007 Lyon, France. Université Lyon 1, 69007 Lyon, France. CNRS, UMR5308, 69007 Lyon, France. mark.smyth@qimrberghofer.edu.au thierry.walzer@inserm.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Walzer
mesh_terms: D000818:Animals; D006801:Humans; D007111:Immunity, Cellular; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*
chemical_list: C569274:IL15 protein, human; D019409:Interleukin-15; D016212:Transforming Growth Factor beta; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases