TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway.
Identifieur interne : 002293 ( PubMed/Corpus ); précédent : 002292; suivant : 002294TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway.
Auteurs : Sébastien Viel ; Antoine Marçais ; Fernando Souza-Fonseca Guimaraes ; Roisin Loftus ; Jessica Rabilloud ; Morgan Grau ; Sophie Degouve ; Sophia Djebali ; Amélien Sanlaville ; Emily Charrier ; Jacques Bienvenu ; Julien C. Marie ; Christophe Caux ; Jacqueline Marvel ; Liam Town ; Nicholas D. Huntington ; Laurent Bartholin ; David Finlay ; Mark J. Smyth ; Thierry WalzerSource :
- Science signaling [ 1937-9145 ] ; 2016.
English descriptors
- KwdEn :
- Animals, Humans, Immunity, Cellular, Interleukin-15 (immunology), Killer Cells, Natural (immunology), Killer Cells, Natural (pathology), Lymphocyte Activation, Mice, Mice, Knockout, Neoplasms, Experimental (genetics), Neoplasms, Experimental (immunology), Signal Transduction (immunology), TOR Serine-Threonine Kinases (genetics), TOR Serine-Threonine Kinases (immunology), Transforming Growth Factor beta (genetics), Transforming Growth Factor beta (immunology).
- MESH :
- chemical , genetics : TOR Serine-Threonine Kinases, Transforming Growth Factor beta.
- chemical , immunology : Interleukin-15, TOR Serine-Threonine Kinases, Transforming Growth Factor beta.
- genetics : Neoplasms, Experimental.
- immunology : Killer Cells, Natural, Neoplasms, Experimental, Signal Transduction.
- pathology : Killer Cells, Natural.
- Animals, Humans, Immunity, Cellular, Lymphocyte Activation, Mice, Mice, Knockout.
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.
DOI: 10.1126/scisignal.aad1884
PubMed: 26884601
Links to Exploration step
pubmed:26884601Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway.</title><author><name sortKey="Viel, Sebastien" sort="Viel, Sebastien" uniqKey="Viel S" first="Sébastien" last="Viel">Sébastien Viel</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Marcais, Antoine" sort="Marcais, Antoine" uniqKey="Marcais A" first="Antoine" last="Marçais">Antoine Marçais</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Guimaraes, Fernando Souza Fonseca" sort="Guimaraes, Fernando Souza Fonseca" uniqKey="Guimaraes F" first="Fernando Souza-Fonseca" last="Guimaraes">Fernando Souza-Fonseca Guimaraes</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Loftus, Roisin" sort="Loftus, Roisin" uniqKey="Loftus R" first="Roisin" last="Loftus">Roisin Loftus</name><affiliation><nlm:affiliation>School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.</nlm:affiliation></affiliation></author><author><name sortKey="Rabilloud, Jessica" sort="Rabilloud, Jessica" uniqKey="Rabilloud J" first="Jessica" last="Rabilloud">Jessica Rabilloud</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Grau, Morgan" sort="Grau, Morgan" uniqKey="Grau M" first="Morgan" last="Grau">Morgan Grau</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Degouve, Sophie" sort="Degouve, Sophie" uniqKey="Degouve S" first="Sophie" last="Degouve">Sophie Degouve</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Djebali, Sophia" sort="Djebali, Sophia" uniqKey="Djebali S" first="Sophia" last="Djebali">Sophia Djebali</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Sanlaville, Amelien" sort="Sanlaville, Amelien" uniqKey="Sanlaville A" first="Amélien" last="Sanlaville">Amélien Sanlaville</name><affiliation><nlm:affiliation>Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.</nlm:affiliation></affiliation></author><author><name sortKey="Charrier, Emily" sort="Charrier, Emily" uniqKey="Charrier E" first="Emily" last="Charrier">Emily Charrier</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Bienvenu, Jacques" sort="Bienvenu, Jacques" uniqKey="Bienvenu J" first="Jacques" last="Bienvenu">Jacques Bienvenu</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Marie, Julien C" sort="Marie, Julien C" uniqKey="Marie J" first="Julien C" last="Marie">Julien C. Marie</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Caux, Christophe" sort="Caux, Christophe" uniqKey="Caux C" first="Christophe" last="Caux">Christophe Caux</name><affiliation><nlm:affiliation>Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.</nlm:affiliation></affiliation></author><author><name sortKey="Marvel, Jacqueline" sort="Marvel, Jacqueline" uniqKey="Marvel J" first="Jacqueline" last="Marvel">Jacqueline Marvel</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Town, Liam" sort="Town, Liam" uniqKey="Town L" first="Liam" last="Town">Liam Town</name><affiliation><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Huntington, Nicholas D" sort="Huntington, Nicholas D" uniqKey="Huntington N" first="Nicholas D" last="Huntington">Nicholas D. Huntington</name><affiliation><nlm:affiliation>The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Bartholin, Laurent" sort="Bartholin, Laurent" uniqKey="Bartholin L" first="Laurent" last="Bartholin">Laurent Bartholin</name><affiliation><nlm:affiliation>Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.</nlm:affiliation></affiliation></author><author><name sortKey="Finlay, David" sort="Finlay, David" uniqKey="Finlay D" first="David" last="Finlay">David Finlay</name><affiliation><nlm:affiliation>School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.</nlm:affiliation></affiliation></author><author><name sortKey="Smyth, Mark J" sort="Smyth, Mark J" uniqKey="Smyth M" first="Mark J" last="Smyth">Mark J. Smyth</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Walzer, Thierry" sort="Walzer, Thierry" uniqKey="Walzer T" first="Thierry" last="Walzer">Thierry Walzer</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:26884601</idno><idno type="pmid">26884601</idno><idno type="doi">10.1126/scisignal.aad1884</idno><idno type="wicri:Area/PubMed/Corpus">002293</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002293</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway.</title><author><name sortKey="Viel, Sebastien" sort="Viel, Sebastien" uniqKey="Viel S" first="Sébastien" last="Viel">Sébastien Viel</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Marcais, Antoine" sort="Marcais, Antoine" uniqKey="Marcais A" first="Antoine" last="Marçais">Antoine Marçais</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Guimaraes, Fernando Souza Fonseca" sort="Guimaraes, Fernando Souza Fonseca" uniqKey="Guimaraes F" first="Fernando Souza-Fonseca" last="Guimaraes">Fernando Souza-Fonseca Guimaraes</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Loftus, Roisin" sort="Loftus, Roisin" uniqKey="Loftus R" first="Roisin" last="Loftus">Roisin Loftus</name><affiliation><nlm:affiliation>School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.</nlm:affiliation></affiliation></author><author><name sortKey="Rabilloud, Jessica" sort="Rabilloud, Jessica" uniqKey="Rabilloud J" first="Jessica" last="Rabilloud">Jessica Rabilloud</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Grau, Morgan" sort="Grau, Morgan" uniqKey="Grau M" first="Morgan" last="Grau">Morgan Grau</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Degouve, Sophie" sort="Degouve, Sophie" uniqKey="Degouve S" first="Sophie" last="Degouve">Sophie Degouve</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Djebali, Sophia" sort="Djebali, Sophia" uniqKey="Djebali S" first="Sophia" last="Djebali">Sophia Djebali</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Sanlaville, Amelien" sort="Sanlaville, Amelien" uniqKey="Sanlaville A" first="Amélien" last="Sanlaville">Amélien Sanlaville</name><affiliation><nlm:affiliation>Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.</nlm:affiliation></affiliation></author><author><name sortKey="Charrier, Emily" sort="Charrier, Emily" uniqKey="Charrier E" first="Emily" last="Charrier">Emily Charrier</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Bienvenu, Jacques" sort="Bienvenu, Jacques" uniqKey="Bienvenu J" first="Jacques" last="Bienvenu">Jacques Bienvenu</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Marie, Julien C" sort="Marie, Julien C" uniqKey="Marie J" first="Julien C" last="Marie">Julien C. Marie</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Caux, Christophe" sort="Caux, Christophe" uniqKey="Caux C" first="Christophe" last="Caux">Christophe Caux</name><affiliation><nlm:affiliation>Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.</nlm:affiliation></affiliation></author><author><name sortKey="Marvel, Jacqueline" sort="Marvel, Jacqueline" uniqKey="Marvel J" first="Jacqueline" last="Marvel">Jacqueline Marvel</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Town, Liam" sort="Town, Liam" uniqKey="Town L" first="Liam" last="Town">Liam Town</name><affiliation><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Huntington, Nicholas D" sort="Huntington, Nicholas D" uniqKey="Huntington N" first="Nicholas D" last="Huntington">Nicholas D. Huntington</name><affiliation><nlm:affiliation>The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Bartholin, Laurent" sort="Bartholin, Laurent" uniqKey="Bartholin L" first="Laurent" last="Bartholin">Laurent Bartholin</name><affiliation><nlm:affiliation>Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.</nlm:affiliation></affiliation></author><author><name sortKey="Finlay, David" sort="Finlay, David" uniqKey="Finlay D" first="David" last="Finlay">David Finlay</name><affiliation><nlm:affiliation>School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.</nlm:affiliation></affiliation></author><author><name sortKey="Smyth, Mark J" sort="Smyth, Mark J" uniqKey="Smyth M" first="Mark J" last="Smyth">Mark J. Smyth</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Walzer, Thierry" sort="Walzer, Thierry" uniqKey="Walzer T" first="Thierry" last="Walzer">Thierry Walzer</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Science signaling</title><idno type="eISSN">1937-9145</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Humans</term><term>Immunity, Cellular</term><term>Interleukin-15 (immunology)</term><term>Killer Cells, Natural (immunology)</term><term>Killer Cells, Natural (pathology)</term><term>Lymphocyte Activation</term><term>Mice</term><term>Mice, Knockout</term><term>Neoplasms, Experimental (genetics)</term><term>Neoplasms, Experimental (immunology)</term><term>Signal Transduction (immunology)</term><term>TOR Serine-Threonine Kinases (genetics)</term><term>TOR Serine-Threonine Kinases (immunology)</term><term>Transforming Growth Factor beta (genetics)</term><term>Transforming Growth Factor beta (immunology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>TOR Serine-Threonine Kinases</term><term>Transforming Growth Factor beta</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Interleukin-15</term><term>TOR Serine-Threonine Kinases</term><term>Transforming Growth Factor beta</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Neoplasms, Experimental</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Killer Cells, Natural</term><term>Neoplasms, Experimental</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Killer Cells, Natural</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Immunity, Cellular</term><term>Lymphocyte Activation</term><term>Mice</term><term>Mice, Knockout</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26884601</PMID><DateCreated><Year>2016</Year><Month>02</Month><Day>17</Day></DateCreated><DateCompleted><Year>2016</Year><Month>11</Month><Day>10</Day></DateCompleted><DateRevised><Year>2016</Year><Month>12</Month><Day>30</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1937-9145</ISSN><JournalIssue CitedMedium="Internet"><Volume>9</Volume><Issue>415</Issue><PubDate><Year>2016</Year><Month>Feb</Month><Day>16</Day></PubDate></JournalIssue><Title>Science signaling</Title><ISOAbbreviation>Sci Signal</ISOAbbreviation></Journal><ArticleTitle>TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway.</ArticleTitle><Pagination><MedlinePgn>ra19</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1126/scisignal.aad1884</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>Copyright © 2016, American Association for the Advancement of Science.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Viel</LastName><ForeName>Sébastien</ForeName><Initials>S</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marçais</LastName><ForeName>Antoine</ForeName><Initials>A</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Guimaraes</LastName><ForeName>Fernando Souza-Fonseca</ForeName><Initials>FS</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Loftus</LastName><ForeName>Roisin</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rabilloud</LastName><ForeName>Jessica</ForeName><Initials>J</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Grau</LastName><ForeName>Morgan</ForeName><Initials>M</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Degouve</LastName><ForeName>Sophie</ForeName><Initials>S</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Djebali</LastName><ForeName>Sophia</ForeName><Initials>S</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sanlaville</LastName><ForeName>Amélien</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Charrier</LastName><ForeName>Emily</ForeName><Initials>E</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bienvenu</LastName><ForeName>Jacques</ForeName><Initials>J</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marie</LastName><ForeName>Julien C</ForeName><Initials>JC</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Caux</LastName><ForeName>Christophe</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marvel</LastName><ForeName>Jacqueline</ForeName><Initials>J</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Town</LastName><ForeName>Liam</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Huntington</LastName><ForeName>Nicholas D</ForeName><Initials>ND</Initials><AffiliationInfo><Affiliation>The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bartholin</LastName><ForeName>Laurent</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Immunology Virology and Inflammation Department, INSERM U1052, CNRS 5286 Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Finlay</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Smyth</LastName><ForeName>Mark J</ForeName><Initials>MJ</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Walzer</LastName><ForeName>Thierry</ForeName><Initials>T</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>02</Month><Day>16</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Sci Signal</MedlineTA><NlmUniqueID>101465400</NlmUniqueID><ISSNLinking>1945-0877</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C569274">IL15 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019409">Interleukin-15</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016212">Transforming Growth Factor beta</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546842">MTOR protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546843">mTOR protein, mouse</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007111" MajorTopicYN="Y">Immunity, Cellular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019409" MajorTopicYN="N">Interleukin-15</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007694" MajorTopicYN="N">Killer Cells, Natural</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008213" MajorTopicYN="Y">Lymphocyte Activation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018345" MajorTopicYN="N">Mice, Knockout</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009374" MajorTopicYN="N">Neoplasms, Experimental</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016212" MajorTopicYN="N">Transforming Growth Factor beta</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>2</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>2</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>11</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26884601</ArticleId><ArticleId IdType="pii">9/415/ra19</ArticleId><ArticleId IdType="doi">10.1126/scisignal.aad1884</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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