TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway

Viel, Sebastien, Marcais, Antoine, Guimaraes, Fernando Souza-Fonseca, Loftus, Roisin, Rabilloud, Jessica, Grau, Morgan, Degouve, Sophie, Djebali, Sophia, Sanlaville, Amelien, Charrier, Emily, Bienvenu, Jacques, Marie, Julien C., Caux, Christophe, Marvel, Jacqueline, Town, Liam, Huntington, Nicholas D., Bartholin, Laurent, Finlay, David, Smyth, Mark J. and Walzer, Thierry (2016) TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway. Science Signaling, 9 415: . doi:10.1126/scisignal.aad1884

Author Viel, Sebastien
Marcais, Antoine
Guimaraes, Fernando Souza-Fonseca
Loftus, Roisin
Rabilloud, Jessica
Grau, Morgan
Degouve, Sophie
Djebali, Sophia
Sanlaville, Amelien
Charrier, Emily
Bienvenu, Jacques
Marie, Julien C.
Caux, Christophe
Marvel, Jacqueline
Town, Liam
Huntington, Nicholas D.
Bartholin, Laurent
Finlay, David
Smyth, Mark J.
Walzer, Thierry
Title TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway
Journal name Science Signaling   Check publisher's open access policy
ISSN 1945-0877
Publication date 2016-02-16
Year available 2016
Sub-type Article (original research)
DOI 10.1126/scisignal.aad1884
Open Access Status Not Open Access
Volume 9
Issue 415
Total pages 13
Place of publication Washington, DC, United States
Publisher American Association for the Advancement of Science
Language eng
Subject 1303 Biochemistry
1312 Molecular Biology
1307 Cell Biology
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 themetabolic 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.
Keyword Growth factor beta
Natural killer cells
Regulatory T cells
Dendritic cells
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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Sub-type: Article (original research)
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