NKp46 and NKG2D Recognition of Infected Dendritic Cells Is Necessary for NK Cell Activation in the Human Response to Influenza Infection

Abstract

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-α was mainly responsible for enhanced NK cytolysis and also important for CD69 up-regulation, whereas IL-12 was necessary for enhancing IFN-γ production. Increased CD69 expression and IFN-γ 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-γ 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.

Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses

“…Our study extends the results of previous publications that used similar in vitro infection systems (38,47 (47). This may be explained, at least in part, by differences in IAV-specific memory T cell responses, because T cells were not depleted in the latter study and T cell-derived IL-2 was clearly shown to enhance NK cell responses.…”

“…NK cells are thought to play an important role early after IAV infection (37,38), and impaired NK cell responses are associated with higher susceptibility to IAV infection in mice (39). Vaccination with inactivated or attenuated virus induces significant IFN-γ responses by NK cells in young children (40), and NK cells can be directly activated by binding of the influenza hemagglutinin to the NK cytotoxicity receptors NKp44 and NKp46 (41,42).…”

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

“…5-7 NKp46 is encoded by Ncr1 and associates with the ITAM-containing CD3ζ or FcRγ polypeptides. Several endogenous ligands of NKp46 have been described including the complement factor P, 8 the intracellular filamentous cytoskeletal protein vimentin expressed on the surface of Mycobacterium tuberculosis –infected monocytes, 9 and several viral proteins such as hemagglutinin and hemagglutinin neuraminidases of the influenza, 10,11 Sendai, 12 Newcastle disease, 13 ectromelia and vaccinia viruses. 14 NKp46 was also shown to recognize PfEMP1 of Plasmodium falciparum , 14 an unknown ligand from Fusobacterium nucleatum , 15 adhesins from Candida glabrata .…”

Sweet Is the Memory of Past Troubles: NK Cells Remember

“…This condition limits the number and diversity of NK receptors and would argue against the ability of NK cells to specifically recognize such a diverse array of antigens via specific receptors. Although the activating receptor NKp46 has been reported to bind to the influenza protein hemagglutinin (HA) (Gazit et al 2006;Draghi et al 2007), Paust et al (2010) showed that HA was not required for NK cell-mediated contact hypersensitivity recall responses to influenza virus-like particles. No specific receptors have been identified for HIV or VSV on NK cells, and given that HIV is not a pathogen of mice, there is no selective pressure for the evolution of a germline-encoded receptor for HIV.…”

“…Gazit et al (2006) reported that mice bearing a homozygous loss-of-function mutation in Ncr1 (NKp46) succumbed to infection earlier than wild-type mice, with higher viral burdens. The interaction between NKp46 and influenza surface protein hemagglutinin (HA) in vitro has also been described (Draghi et al 2007). We examined whether NKp46 recognition of influenza-infected cells could drive the proliferation of NK cells and generate influenza-specific NK cell memory.…”