Killing of Avian and Swine Influenza Virus by Natural Killer Cells

Achdout, Hagit; Meningher, Tal; Hirsh, Shira; Glasner, Ariella; Bar-On, Yotam; Gur, Chamutal; Porgador, Angel; Mendelson, Michal; Mandelboim, Michal; Mandelboim, Ofer

doi:10.1128/jvi.02289-09

Cited by 60 publications

(67 citation statements)

References 40 publications

(62 reference statements)

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“…Indeed, whereas the influenza HA is a lectin, and its interaction with NKp46/NCR1 causes direct killing of the infected cells (8,17), other ligands, such as the ligand found on MCA-induced sarcoma, cause indirect killing by cytokine secretion (14). Notably, the ligand on MCA-transformed cells undergoes immune editing by NKp46/NCR1 pressure (14), whereas the ligand on D122 cells described in this study apparently does not.…”

Section: Discussionmentioning

confidence: 74%

“…In this study, we show that NKp46/NCR1 recognizes an unknown ligand(s) expressed by the metastatic cell lines B16 and D122, as well as by D122 tumors and metastases. We demonstrate that unlike the HA protein that interacts with the sialic residues of the NKp46/NCR1 (7,8,17), the unknown D122 ligand(s) of NKp46/NCR1 binds this receptor in a sialic acidindependent manner. We further demonstrate that the tumor ligand(s) expressed by PD1.6 and D122 cells contains a protein component.…”

Section: Discussionmentioning

confidence: 99%

“…It was previously shown that both the human NKp46 and the mouse NCR1 recognize the influenza virus HA in a sialic acid-dependent manner (7,8,15,17). To study whether the unknown NKp46/NCR1 ligand(s) expressed on D122 cells is a lectin, with properties similar to those of HA, we treated the NCR1-Ig fusion proteins with NA to remove sialic acid residues.…”

Section: Immune Editing and Tumor Ligand(s) Characteristicsmentioning

confidence: 99%

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Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Glasner¹,

Ghadially²,

Gur³

et al. 2012

The Journal of Immunology

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141

119

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NK cells employ a variety of activating receptors to kill virally infected and tumor cells. Prominent among these receptors are the natural cytotoxicity receptors (NCRs) (NKp30, NKp44, and NKp46), of which only NKp46 has a mouse ortholog (NCR1). The tumor ligand(s) of NKp46/NCR1 is still unknown, but it was shown that the human NKp46 and the mouse NCR1 are involved in tumor eradication both in vitro and in vivo. Whether any of the NK activating receptors is involved in the prevention of tumor metastasis is unknown. To address this question, we studied the activity of the NK cell receptor NKp46/NCR1 in two spontaneous metastasis models, the B16F10.9 melanoma (B16) and the Lewis lung carcinoma (D122) in the NCR1 knockout mouse that was generated by our group, in various in vitro and in vivo assays. We demonstrated that all B16 and D122 tumors, including those generated in vivo, express an unknown ligand(s) for NKp46/NCR1. We have characterized the properties of the NKp46/NCR1 ligand(s) and demonstrated that NKp46/NCR1 is directly involved in the killing of B16 and D122 cells. Importantly, we showed in vivo that NKp46/NCR1 plays an important role in controlling B16 and D122 metastasis. Thus, to our knowledge, in this study we provide the first evidence for the direct involvement of a specific NK killer receptor in preventing tumor metastasis.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Immune Editing and Tumor Ligand(s) Characteristicsmentioning

confidence: 99%

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Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Glasner¹,

Ghadially²,

Gur³

et al. 2012

The Journal of Immunology

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141

119

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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.…”

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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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NKp46 expression discriminates porcine NK cells with different functional properties

et al. 2012

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So far little is known about natural killer (NK) cells in the pig due to the lack of NK cell-specific markers. In this study, we identified the activating receptor NKp46 (CD335) in swine with newly developed monoclonal antibodies (mAbs) for more detailed studies on NK cells in this species. The NKp46 mAbs showed a specific reactivity with a distinct population of perforin + CD2 + CD3 − CD8α + CD16 + lymphocytes. In spleen and liver, an additional subset of CD8α dim/− lymphocytes with increased NKp46 expression was observed. Surprisingly, we could identify NKp46 − cells with an NK cell phenotype in all animals analyzed. These lymphocytes showed comparable cytolytic activity against xenogeneic and allogeneic target cells as NKp46 + NK cells. In contrast, NKp46 + NK cells produced several fold higher levels of interferon-γ (IFN-γ) than the NKp46 − cells after cytokine stimulation. Furthermore, an activation-dependent induction of NKp46 expression in formerly NKp46 − cells after stimulation with interleukin-2 (IL-2), IL-12, and IL-18 could be shown. In summary, our data indicate that NKp46 is not expressed by all porcine NK cells and that NKp46 discriminates porcine NK cells differing in regard to cytokine production, which challenges the paradigm of NKp46 as a comprehensive marker for NK cells across different mammalian species.Keywords: NK cell · NKp46 · Swine Supporting Information available online IntroductionNatural killer (NK) cells are a highly specialized subpopulation of lymphocytes that play a crucial role in the early phase of immune responses. So far little is known about NK cells in swine. The phenotype of porcine NK cells was recently described as perforin + CD2 + CD3 − CD4 − CD5 − CD6 − CD8α + CD8ß − CD11b + CD16 + and it was observed that these cells exhibit natural cytotoxicity against NK-susceptible targets [1][2][3][4]. Likewise, the Correspondence: Dr. Armin Saalmüller e-mail: armin.saalmueller@vetmeduni.ac.at involvement of porcine NK cells has been reported in immune responses against parasitic and viral infections [5][6][7][8][9]. But since porcine NK cells share several phenotypic markers with other cell populations such as NKT cells, TCR-γδ T cells, and myeloid cells [3,4], the precise detection, isolation, and more detailed functional characterization of porcine NK cells has been thus far difficult. Thus, the identification of a discrete and unifying marker for this cell population in swine would be highly beneficial.NKp46 (CD335, NCR1), a member of the natural cytotoxicity receptor (NCR) family, is specifically expressed on NK cells, * These authors contributed equally to this work. , the triggering receptor NKp46 might also be a good candidate molecule for the specific identification of NK cells in swine. Porcine NKp46 was previously described as being encoded in the porcine leukocyte receptor complex on chromosome 6 [24]. The first expression analysis at the mRNA level revealed that the overall sequence and tissue distribution of porcine NKp46 was comparable with that of other species [2...

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Killing of Avian and Swine Influenza Virus by Natural Killer Cells

Cited by 60 publications

References 40 publications

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

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

NKp46 expression discriminates porcine NK cells with different functional properties

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Killing of Avian and Swine Influenza Virus by Natural Killer Cells

Cited by 60 publications

References 40 publications

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

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

NKp46 expression discriminates porcine NK cells with different functional properties

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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