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      High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          NK cell education is the process through which chronic engagement of inhibitory NK cell receptors by self MHC-I molecules preserves cellular responsiveness. The molecular mechanisms responsible for NK cell education remain unclear. Here, we show that mouse NK cell education is associated with a higher basal activity of the mTOR/Akt pathway, commensurate to the number of educating receptors. This higher activity was dependent on the SHP-1 phosphatase and essential for the improved responsiveness of reactive NK cells. Upon stimulation, the mTOR/Akt pathway amplified signaling through activating NK cell receptors by enhancing calcium flux and LFA-1 integrin activation. Pharmacological inhibition of mTOR resulted in a proportional decrease in NK cell reactivity. Reciprocally, acute cytokine stimulation restored reactivity of hyporesponsive NK cells through mTOR activation. These results demonstrate that mTOR acts as a molecular rheostat of NK cell reactivity controlled by educating receptors and uncover how cytokine stimulation overcomes NK cell education.

          eLife digest

          The cells of the immune system patrol the body to detect and destroy harmful microbes and diseased cells. Natural killer cells are immune cells with a natural capacity to kill infected or cancerous cells, as their name suggests. Importantly, they do so while sparing the surrounding healthy cells.

          As natural killer cells mature they go through an “education” process to learn to distinguish between normal and abnormal cells. During education, the natural killer cells interact continuously with nearby healthy cells. However, it remains unknown how these interactions change the natural killer cells, or how these changes control their killing activity.

          Marçais et al. now show that a protein called mTOR is essential to the education of natural killer cells. Comparing natural killer cells that had or had not completed the education process revealed that mTOR is more active in the educated cells. Moreover, inhibiting the activity of mTOR caused educated natural killer cells to lose their ability to identify diseased cells, while stimulating mTOR activity in uneducated natural killer cells mimicked the education process, allowing them to recognize and eliminate diseased host cells.

          Certain nutrients are known to control the activity of mTOR, which suggests these nutrients could also affect how natural killer cells develop. In addition, manipulating the activity of mTOR could be used to control the response of natural killer cells to diseased host cells, and so could form part of treatments for cancer and infectious diseases. However, given that mTOR plays numerous roles within different body cells, any potential therapies that are developed would need to be able to manipulate mTOR specifically in natural killer cells.

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          Most cited references 57

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          Functions of natural killer cells.

          Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Recent research highlights the fact that NK cells are also regulatory cells engaged in reciprocal interactions with dendritic cells, macrophages, T cells and endothelial cells. NK cells can thus limit or exacerbate immune responses. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.
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            Innate lymphoid cells--a proposal for uniform nomenclature.

            Innate lymphoid cells (ILCs) are a family of developmentally related cells that are involved in immunity and in tissue development and remodelling. Recent research has identified several distinct members of this family. Confusingly, many different names have been used to characterize these newly identified ILC subsets. Here, we propose that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.
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              Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton.

              The mammalian TOR (mTOR) pathway integrates nutrient- and growth factor-derived signals to regulate growth, the process whereby cells accumulate mass and increase in size. mTOR is a large protein kinase and the target of rapamycin, an immunosuppressant that also blocks vessel restenosis and has potential anticancer applications. mTOR interacts with the raptor and GbetaL proteins to form a complex that is the target of rapamycin. Here, we demonstrate that mTOR is also part of a distinct complex defined by the novel protein rictor (rapamycin-insensitive companion of mTOR). Rictor shares homology with the previously described pianissimo from D. discoidieum, STE20p from S. pombe, and AVO3p from S. cerevisiae. Interestingly, AVO3p is part of a rapamycin-insensitive TOR complex that does not contain the yeast homolog of raptor and signals to the actin cytoskeleton through PKC1. Consistent with this finding, the rictor-containing mTOR complex contains GbetaL but not raptor and it neither regulates the mTOR effector S6K1 nor is it bound by FKBP12-rapamycin. We find that the rictor-mTOR complex modulates the phosphorylation of Protein Kinase C alpha (PKCalpha) and the actin cytoskeleton, suggesting that this aspect of TOR signaling is conserved between yeast and mammals.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                06 September 2017
                2017
                : 6
                Affiliations
                [1 ]CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research LyonFrance
                [2 ]Inserm, U1111 LyonFrance
                [3 ]Ecole Normale Supérieure de Lyon LyonFrance
                [4 ]Université Lyon 1 LyonFrance
                [5 ]deptCNRS UMR5308 LyonFrance
                [6 ]deptCentre for Hematology and Regenerative Medicine, Department of Medicine Karolinska Institutet, Karolinska University Hospital Huddinge StockholmSweden
                [7 ]deptLaboratoire d’Immunologie Hospices Civils de Lyon, Centre Hospitalier Lyon Sud LyonFrance
                [8 ]Innate-Pharma MarseilleFrance
                [9 ]Aix-Marseille Université, CNRS, INSERM, CIML MarseilleFrance
                [10 ]APHM, Hôpital de la Timone, Service d’Immunologie MarseilleFrance
                [11 ]deptBroegelmann Research Laboratory, The Gades Institute University of Bergen BergenNorway
                Howard Hughes Medical Institute, Washington University School of Medicine United States
                Howard Hughes Medical Institute, Washington University School of Medicine United States
                Article
                26423
                10.7554/eLife.26423
                5628014
                28875936
                © 2017, Marçais et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Product
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001665, Agence Nationale de la Recherche;
                Award ID: ANR-16-CE15-0005-01 Bank
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100010663, H2020 European Research Council;
                Award ID: 281025 Dironaki
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Immunology
                Custom metadata
                Chronic engagement of Natural killer cell inhibitory receptors by MHC-I molecules maintains a high activity of the mTOR pathway allowing subsequent amplification of signaling through activating receptors upon acute stimulation.

                Life sciences

                cell signaling, mtor, education, mouse, activation threshold, natural killer

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