NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells

Sivori, Simona; Pende, Daniela; Bottino, Cristina; Marcenaro, Emanuela; Pessino, A.; Biassoni, Roberto; Moretta, Lorenzo; Moretta, Alessandro

doi:10.1002/(sici)1521-4141(199905)29:05<1656::aid-immu1656>3.0.co;2-1

Cited by 374 publications

(353 citation statements)

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“…As shown previously, the spontaneous NK-mediated killing of these target cells is at least in part dependent upon NKp46 engagement by murine cell ligand(s) expressed on P815 [19]. Indeed, blocking of this receptor by the use of anti-NKp46 mAb of the IgM isotype was shown to down-regulate NKmediated killing of P815 cells by NK clones or polyclonal NK cells [19]. Thus, it is conceivable that during redirected-killing experiments in which NK cells are stimulated by IgG mAb specific for one or another triggering receptor, the interaction between NKp46 and its putative murine ligand(s) may provide activating signals that cooperate with the stimulatory mAb.…”

Section: Nk Cell Redirected Killing Of P815 Target Cells By Anti-nkg2mentioning

confidence: 57%

“…A classical target cell that is commonly used for redirected killing analysis is represented by the murine mastocytoma P815. As shown previously, the spontaneous NK-mediated killing of these target cells is at least in part dependent upon NKp46 engagement by murine cell ligand(s) expressed on P815 [19]. Indeed, blocking of this receptor by the use of anti-NKp46 mAb of the IgM isotype was shown to down-regulate NKmediated killing of P815 cells by NK clones or polyclonal NK cells [19].…”

Section: Nk Cell Redirected Killing Of P815 Target Cells By Anti-nkg2mentioning

confidence: 57%

“…However, it is well known that during this type of assay, additional receptor-ligand interactions occur, including [19]. IgG1 mAb were used at the indicated dilution of hybridoma culture supernatant whereas the IgM mAb was used as undiluted culture supernatant.…”

Section: Nk Cell Redirected Killing Of P815 Target Cells By Anti-nkg2mentioning

confidence: 99%

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Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors

et al. 2004

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NKG2D and natural cytotoxicity receptors (NCR) are essential recognition structures that mediate NK cell activation. NKG2D and NCR signaling is achieved through membrane association with signaling adaptors. The adaptors that associate with NCR -such as CD3´, FcR + and KARAP/DAP12 -bear intracytoplasmic immunoreceptor tyrosine-based activation motifs that activate Syk protein tyrosine kinases. Human NKG2D associates with the DAP10 transmembrane adaptor, which bears a YxxM motif and activates the phosphatidylinositol 3-kinase pathway. In the mouse, a short NKG2D-S isoform, generated by Nkg2d alternative splicing, can associate with either DAP10 or KARAP/DAP12. Here, we report that neither short human NKG2D alternative transcripts nor NKG2D association with KARAP/ DAP12 was detected in activated human NK cells. Despite these results, NK cell triggering by both recombinant soluble NKG2D ligands (MICA and ULBP-1) and anti-NCR crosslinking antibodies induced similar CD25 expression, NK cell proliferation and cytokine production. In contrast, NKG2D triggering by anti-NKG2D antibodies did not lead to any detectable activation signals. These data thus show that target recognition via NKG2D or NCR triggers all aspects of NK activation, and pave the way for further dissection of the signaling pathways induced by NK cell recognition of ULBP-1 and MICA. The first three authors contributed equally to this work. Abbreviations: CFSE:Carboxyfluoresceine diacetate succinimidyl ester ITAM: Immunoreceptor tyrosine-based activation motif NCR: Natural cytotoxicity receptor RLM 5'-RACE: RNA-ligase-mediated rapid amplification of cDNA ends

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Section: Nk Cell Redirected Killing Of P815 Target Cells By Anti-nkg2mentioning

confidence: 57%

Section: Nk Cell Redirected Killing Of P815 Target Cells By Anti-nkg2mentioning

confidence: 57%

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Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors

et al. 2004

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“…Because surface expression of NK receptors often corresponds to NK maturation and function, 12,13,27 we next analyzed the expression patterns of several receptors in NKp46 High and NKp46 Dim NK-cell subsets (Supporting Fig. 1A).…”

Section: Resultsmentioning

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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“…In contrast, as shown in Figure 5 b , Aneustat very markedly reduced the numbers of FOXP3 + Treg cells (by >90%), thereby markedly increasing the ratio of intratumoral patient anticancer T cells to Treg cells in the Aneustat‐treated tissues. NK cells and MDSCs were identified by staining with NCR1 and CD33, respectively 35, 36, 37. As shown in Figure 6, the Aneustat‐treated tissues showed higher NCR1 + NK cell numbers compared to controls, whereas the MDSCs in the Aneustat‐treated tissues were lower in number than in the controls.…”

Section: Resultsmentioning

confidence: 95%

Aneustat (OMN54) has aerobic glycolysis‐inhibitory activity and also immunomodulatory activity as indicated by a first‐generation PDX prostate cancer model

Xue

Dong

et al. 2018

Intl Journal of Cancer

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Aneustat (OMN54) is a multivalent, botanical anticancer candidate therapeutic. A recent Phase‐I clinical trial has indicated that it is well tolerated by patients and has immunomodulatory activity. In our study, using in vitro and in vivo prostate cancer models, we investigated Aneustat with regard to effects on (i) cancer‐generated immunosuppression based on aerobic glycolysis leading to acidification of the tumor microenvironment, and (ii) immune‐related processes such as macrophage differentiation and shifts in the intratumoral levels of host immune cells. Aneustat markedly reduced glucose consumption, lactic acid secretion, glycolysis‐related gene expressions and proliferation of human LNCaP prostate cancer cells. In addition, Aneustat induced differentiation of RAW264.7 macrophages to the M1 anticancer phenotype. Treatment of LNCaP xenografts and first‐generation patient‐derived prostate cancer tissue xenografts with Aneustat in both cases led to a marked shift in intratumoral host (mouse/patient) immune cell levels: a higher ratio of cytotoxic CD8+ T/Treg cells, higher numbers of NK cells, lower numbers of Treg cells and MDSCs, i.e. changes favoring the host anticancer immune response. Taken together, the data indicate that Aneustat has immunomodulatory activity based on inhibition of aerobic glycolysis which in patients may lead to reduction of cancer‐induced immunosuppression. Furthermore, first‐generation patient‐derived cancer tissue xenograft models may be used for screening compounds for immunomodulatory activity.

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NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells

Cited by 374 publications

References 21 publications

Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors

Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors

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

Aneustat (OMN54) has aerobic glycolysis‐inhibitory activity and also immunomodulatory activity as indicated by a first‐generation PDX prostate cancer model

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NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells

Cited by 374 publications

References 21 publications

Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors

Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors

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

Aneustat (OMN54) has aerobic glycolysis‐inhibitory activity and also immunomodulatory activity as indicated by a first‐generation PDX prostate cancer model

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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