title: Regulatory Dendritic Cells Restrain NK Cell IFN-γ Production through Mechanisms Involving NKp46, IL-10, and MHC Class I-Specific Inhibitory Receptors.
abstract: Cross-talk between mature dendritic cells (mDC) and NK cells through the cell surface receptors NKp30 and DNAM-1 leads to their reciprocal activation. However, the impact of regulatory dendritic cells (regDC) on NK cell function remains unknown. As regDC constrain the immune response in different physiological and pathological conditions, the aim of this work was to investigate the functional outcome of the interaction between regDC and NK cells and the associated underlying mechanisms. RegDC generated from monocyte-derived DC treated either with LPS and dexamethasone, vitamin D3, or vitamin D3 and dexamethasone instructed NK cells to secrete lower amounts of IFN-γ than NK cells exposed to mDC. Although regDC triggered upregulation of the activation markers CD69 and CD25 on NK cells, they did not induce upregulation of CD56 as mDC, and silenced IFN-γ secretion through mechanisms involving insufficient secretion of IL-18, but not IL-12 or IL-15 and/or induction of NK cell apoptosis. Blocking experiments demonstrated that regDC curb IFN-γ secretion by NK cells through a dominant suppressive mechanism involving IL-10, NK cell inhibitory receptors, and, unexpectedly, engagement of the activating receptor NKp46. Our findings unveil a previously unrecognized cross-talk through which regDC shape NK cell function toward an alternative activated phenotype unable to secrete IFN-γ, highlighting the plasticity of NK cells in response to tolerogenic stimuli. In addition, our findings contribute to identify a novel inhibitory role for NKp46 in the control of NK cell function, and have broad implications in the resolution of inflammatory responses and evasion of antitumor responses.
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina;
authors.forename: Raúl G
authors.initials: RG
authors.lastname: Spallanzani
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina;
authors.forename: Nicolás I
authors.initials: NI
authors.lastname: Torres
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina; Cátedra de Inmunología, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 1900 La Plata, Argentina;
authors.forename: Damián E
authors.initials: DE
authors.lastname: Avila
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina;
authors.forename: Andrea
authors.initials: A
authors.lastname: Ziblat
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina;
authors.forename: Ximena L Raffo
authors.initials: XL
authors.lastname: Iraolagoitia
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina;
authors.forename: Lucas E
authors.initials: LE
authors.lastname: Rossi
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina;
authors.forename: Carolina I
authors.initials: CI
authors.lastname: Domaica
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina;
authors.forename: Mercedes B
authors.initials: MB
authors.lastname: Fuertes
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina; Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina; and.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, C1121ABG Buenos Aires, Argentina nzwirner@ibyme.conicet.gov.ar.
authors.forename: Norberto W
authors.initials: NW
authors.lastname: Zwirner
mesh_terms: D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000276:immunology / Q000494:pharmacology; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003907:Dexamethasone / Q000276:immunology / Q000494:pharmacology; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000276:immunology / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000276:immunology* / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000276:immunology; D014815:Vitamins / Q000276:immunology / Q000494:pharmacology
chemical_list: D061025:Costimulatory and Inhibitory T-Cell Receptors; D005938:Glucocorticoids; D015395:Histocompatibility Antigens Class I; D020382:Interleukin-18; D008070:Lipopolysaccharides; D055627:Natural Cytotoxicity Triggering Receptor 1; D014815:Vitamins; D016753:Interleukin-10; D018664:Interleukin-12; D002762:Cholecalciferol; D003907:Dexamethasone; D007371:Interferon-gamma