NKp46 and NKG2D recognition of infected dendritic cells is necessary for NK cell activation in the human response to influenza infection.
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-alpha was mainly responsible for enhanced NK cytolysis and also important for CD69 up-regulation, whereas IL-12 was necessary for enhancing IFN-gamma production. Increased CD69 expression and IFN-gamma 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-gamma 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.
Draghi
Monia
M
Department of Structural Biology, 299 Campus Drive West, Stanford University School of Medicine, Stanford, CA 94305, USA. mdraghi@stanford.edu
Pashine
Achal
A
Sanjanwala
Bharati
B
Gendzekhadze
Ketevan
K
Cantoni
Claudia
C
Cosman
David
D
Moretta
Alessandro
A
Valiante
Nicholas M
NM
Parham
Peter
P
D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D006388:Hemagglutinins / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007251:Influenza, Human / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002352:Carrier Proteins; D006388:Hemagglutinins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D011070:Poly I-C; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D014764:Viral Proteins; D000099192:CD69 Antigens; C527085:KLRK1 protein, human; C112260:NCR1 protein, human