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

Abstract : Transforming growth factor-beta (TGF-beta) 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-beta 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-beta in vitro blocked interleukin-15 (IL-15)-induced activation of mTOR. TGF-beta 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-beta signaling or depletion of mTOR arrested NK cell development, whereas deletion of the TGF-beta receptor subunit TGF-betaRII enhanced mTOR activity and the cytotoxic activity of the NK cells in response to IL-15. Suppression of TGF-beta 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
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Submitted on : Saturday, May 19, 2018 - 11:34:18 AM
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Sébastien Viel, Antoine Marçais, Fernando Souza-Fonseca Guimaraes, Roisin Loftus, Jessica Rabilloud, et al.. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Science Signaling, American Association for the Advancement of Science, 2016, 9 (415), pp.ra19-ra19. ⟨http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aad1884⟩. ⟨10.1126/scisignal.aad1884⟩. ⟨hal-01796190⟩

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