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* Department of Structural Biology and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
Novartis Vaccines and Diagnostics, Novartis Corporation, Emeryville, CA 94608;
Department of Experimental Medicine, Istituto Giannina Gaslini, University of Genova, Genova, Italy; and
Department of Oncology, Amgen, Seattle, WA 98101
At an early phase of viral infection, contact and cooperation between dendritic cells (DCs) and NK cells activates innate immunity, and also influences recruitment, when needed, of adaptive immunity. Influenza, an adaptable fast-evolving virus, annually causes acute, widespread infections that challenge the innate and adaptive immunity of humanity. In this study, we dissect and define the molecular mechanisms by which influenza-infected, human DCs activate resting, autologous NK cells. Three events in NK cell activation showed different requirements for soluble mediators made by infected DCs and for signals arising from contact with infected DCs. IFN-
was mainly responsible for enhanced NK cytolysis and also important for CD69 up-regulation, whereas IL-12 was necessary for enhancing IFN-
production. Increased CD69 expression and IFN- production, but not increased cytolysis, required recognition of influenza-infected DCs by two NK cell receptors: NKG2D and NKp46. Abs specific for these receptors or their known ligands (UL16-binding proteins 1–3 class I-like molecules for NKG2D and influenza hemagglutinin for NKp46) inhibited CD69 expression and IFN- production. Activation of NK cells by influenza-infected DCs and polyinosinic:polycytidylic acid (poly(I:C))-treated DCs was distinguished. Poly(I:C)-treated DCs did not express the UL16-binding protein 3 ligand for NKG2D, and in the absence of the influenza hemagglutinin there was no involvement of NKp46.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant P01 AI57229, Project 4 (to P.P.).
2 Address correspondence and reprint request to Dr. Monia Draghi, Department of Structural Biology and Department of Microbiology and Immunology, 299 Campus Drive West, Room D155, Fairchild Building, Stanford University School of Medicine, Stanford, CA 94305; E-mail address: mdraghi{at}stanford.edu or Dr. Peter Parham, Department of Structural Biology and Department of Microbiology and Immunology, 299 Campus Drive West, Room D155, Fairchild Building, Stanford University School of Medicine, Stanford, CA 94305; E-mail address: peropa{at}stanford.edu
3 Current address: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304.
4 Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; HA, hemagglutinin; MIC, MHC class I chain-related protein; ULBP, UL16-binding protein; HAU, HA unit; poly(I:C), polyinosinic:polycytidylic acid; NP, nucleoprotein; PI, propidium iodide; S1P1, sphingosine 1-phosphate receptor-1; MFI, mean fluorescence intensity.
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