The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46

Arnon, Tal I.; Achdout, Hagit; Lieberman, Niva; Gazit, Roi; Gonen‐Gross, Tsufit; Katz, Gil; Bar-Ilan, Ahuva; Bloushtain, Noga; Lev, Marianna; Joseph, Aviva; Kedar, Eli; Porgador, Angel; Mandelboim, Ofer

doi:10.1182/blood-2003-05-1716

Cited by 221 publications

(310 citation statements)

References 39 publications

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“…9). Although we cannot rule out the possibility that NKp46 binds additional cellular ligand(s) induced by the virus (75) or that HA may serve as a ligand for other NK receptors, our results are consistent with previous reports suggesting that HA is a ligand for NKp46 (43,44). Moreover, we extend these original findings by placing potential NKp46-HA interactions in the context of NK-DC cooperation (76).…”

Section: Discussionsupporting

confidence: 90%

“…Of the latter, NKp46 and NKp30 are on most human peripheral blood NK cells, whereas, NKp44 is only on activated NK cells (37,42). Although endogenous natural cytotoxicity receptor ligands remain undetermined, NKp46 binds the influenza hemagglutinin (HA) protein as well as the HA-neuraminidase of parainfluenzavirus (43,44). NKG2D mediates NK cytolysis of tumors and CMVinfected cells (45,46).…”

Section: Nkp46 and Nkg2d Recognition Of Infected Dendritic Cells Is Nmentioning

confidence: 99%

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

Draghi

Pashine

Sanjanwala

et al. 2007

The Journal of Immunology

178

167

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Nkp46 and Nkg2d Recognition Of Infected Dendritic Cells Is Nmentioning

confidence: 99%

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

Draghi

Pashine

Sanjanwala

et al. 2007

The Journal of Immunology

178

167

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“…In addition to neutralising antibodies, activation of cytotoxic T-cells natural killer (NK) cells are activated through interaction of the SeV hemagluttin-neuraminidase (HN) protein with the NK cell receptor NKp46 19 having an important role. The effect of SeV on immune modulation is further highlighted in a study by Komary et al, which showed that SeV-transduced dendritic cells can induce persistent NK and CD4-cell-dependent anti-tumor activity.…”

Section: Discussionmentioning

confidence: 99%

Validation of recombinant Sendai virus in a non-natural host model

et al. 2010

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We have previously shown that recombinant Sendai virus (SeV) vector, derived from murine parainfluenza virus, is one of the most efficient vectors for airway gene transfer. We have also shown that SeV-mediated transfection on second administration, although reduced by 60% when compared with levels achieved after a single dose, is still high because of the efficient transfection achieved by SeV vector in murine airways. Here, we show that these levels further decrease on subsequent doses. In addition, we validated SeV vector repeat administration in a non-natural host model, the sheep. As part of these studies we first assessed viral stability in a Pari LC Plus nebuliser, a polyethylene catheter (PEC) and the Trudell AeroProbe. We also compared the distribution of gene expression after PEC and Trudell AeroProbe administration and quantified virus shedding after sheep transduction. In addition, we show that bronchial brushings and biopsies, collected in anaesthetized sheep, can be used to assess SeV-mediated gene expression over time. Similar to mice, gene expression in sheep was transient and had returned to baseline values by day 14. In conclusion, the SeV vector should be strongly considered for lung-related applications requiring a single administration of the vector even though it might not be suitable for diseases requiring repeat administration.

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“…Moreover, we found that intrahepatic frequency of NKp46 High NK cells inversely correlated with HCV loads. Whether NKp46 recognizes a HCV-derived protein [17][18][19][20][21] or interacts with a yet unknown NKp46 ligand, as has been suggested for malignant transformed cells, 40,41 remains to be clarified. However, blocking of NKp46 significantly reduced the capability of both circulating and intrahepatic NK cells to block HCV replication, suggesting a role of NKp46 in the regulation of anti-HCV immune responses.…”

Section: Nk Cells (Supportingmentioning

confidence: 99%

“…Moreover, NKp46 plays an important role in the killing of virus-infected cells by interacting with viral proteins. [17][18][19][20][21] Studies on NKp46 in HCV infection are controversial, because both reduced and increased surface expression have been reported. 5,[7][8][9] In this context, it is of interest that earlier studies showed that the surface expression of NKp46 may vary in different human peripheral blood NK cells, and that the NKp46 phenotype of NK clones correlates with cytolytic activity.…”

mentioning

confidence: 99%

Natural killer p46^Highexpression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

et al. 2012

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Natural killer (NK) cells play a role in the early control and natural course of hepatitis C virus (HCV) infection. NK cell function is regulated by a multitude of receptors, including activating NKp46 receptor. However, reports on NKp46 in hepatitis C are controversial. Therefore, we investigated the hepatic recruitment and function of NKp46(1) NK cells, considering differential surface expression of NKp46 resulting in NKp46 High and NKp46 Dim subsets. Intra-and extrahepatic NK-cell subsets from HCV-infected patients were characterized by flow cytometry. Cytotoxic activity and interferon-gamma (IFN-c) secretion were studied using K-562, P815, and primary hepatic stellate cells as targets. Anti-HCV activity of NK-cell subsets was studied using the replicon system. Density of NKp46 surface expression clearly segregated NKp46 Dim and NKp46 High subsets, which differed significantly with respect to the coexpression of maturation markers and NK-cell receptors. More important, NKp46 High NK cells showed a higher cytolytic activity and stronger IFN-c secretion than NKp46 Dim NK cells. Accordingly, NKp46 High NK cells efficiently blocked HCV replication in vitro. Blocking experiments confirmed an important role for the NKp46 receptor. Furthermore, we found an intrahepatic accumulation of NKp46 High NK cells. Of note, high cytolytic activity of NKp46 High NK cells was also confirmed in the intrahepatic NK-cell population, and the frequency of intrahepatic NKp46 High NK cells was inversely correlated with HCV-RNA levels and fibrosis stage. Conclusions: NKp46 High expression defines a specific NK-cell subset that may be involved in both the suppression of HCV replication and HCV-associated liver damage underpinning the role of NK cells in the immunopathogenesis of HCV. (HEPATOLOGY 2012;56:1201-1213 See Editorial on Page 1197 I nfection with the hepatitis C virus (HCV) often results in chronic liver disease. Elimination of HCV infection requires the coordinated function of the innate and the adaptive immune system. Natural killer (NK) cells constitute a major component of the intrahepatic lymphocyte pool. In contrast to the peripheral blood, which contains approximately 5%-10% NK cells, intrahepatic lymphocytes comprise approximately 30% NK cells, and the percentage of intrahepatic NK cells may increase >50% in liver diseases. 1 Immunogenetic analyses indicate that NK cells may influence the outcome of acute HCV infection as well as immunopathogenesis in chronic hepatitis C (CHC). 2 Accordingly, in vitro studies suggest that NK cells are able to recognize and kill HCV-infected hepatocytes in vivo. 3 However, published data on phenotype and function of NK cells in HCV infection are controversial. [4][5][6][7][8][9][10][11][12][13]

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The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46

Cited by 221 publications

References 39 publications

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

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

Validation of recombinant Sendai virus in a non-natural host model

Natural killer p46^Highexpression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

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The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46

Cited by 221 publications

References 39 publications

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

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

Validation of recombinant Sendai virus in a non-natural host model

Natural killer p46Highexpression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

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Product

Resources

About

Natural killer p46^Highexpression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis