Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection

Crotta, Stefania; Brazzoli, Michela; Piccioli, Diego; Valiante, Nicholas M.; Wack, Andreas

doi:10.1016/j.jhep.2009.11.003

Cited by 72 publications

(54 citation statements)

References 33 publications

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“…Indeed, NK cell absence in humans, or their removal in mice, leads to disseminated herpesvirus, influenza virus, and Ebola virus infections (15)(16)(17)(18). Their relevance in control of virus infections is reflected by the quantity of mechanisms that have been developed to evade NK cell activity, including skewed cytokine production (19,20), reduced NCR expression with an activated NK cell phenotype (21)(22)(23), and NCR ligand shedding or downmodulation on target cells (22,(24)(25)(26)(27). A distinct pattern of NCR expression and induction associates with a benign course of HIV infection in a minority of HIV-infected patients with low or undetectable viremia (HIV controllers [HIC], long-term nonprogressors [LTNP], and elite controllers [EC]) (28)(29)(30) and in chronically hepatitis C virus (HCV)-infected patients who respond to treatment (31,32).…”

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confidence: 99%

Control of the HIV-1 DNA Reservoir Is AssociatedIn VivoandIn Vitrowith NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

Marras¹,

Casabianca

Bozzano

et al. 2017

J Virol

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confidence: 99%

Control of the HIV-1 DNA Reservoir Is AssociatedIn VivoandIn Vitrowith NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

Marras¹,

Casabianca

Bozzano

et al. 2017

J Virol

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“…The recombinant E2 cannot, however, completely represent natural E2 proteins that are immobilized on the lipid bilayer envelope of HCV virions. In fact, naturally expressed E2 proteins on the surface of cell culture-generated infectious HCV particles do not inhibit NK cell function (8,40), unless the cell-free virions themselves are immobilized and concentrated on the surface of a plate (8). This shows the utility of HCV cell culture systems for a close examination of interaction between HCV and immune cells.…”

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confidence: 99%

Cell-to-Cell Contact with Hepatitis C Virus-Infected Cells Reduces Functional Capacity of Natural Killer Cells

Yoon

Lim

Park

et al. 2011

J Virol

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The distinct feature of hepatitis C virus (HCV) infection is. On the other hand, inhibition of activating receptor expression on NK cell surfaces may also suppress NK cell responses (39). Because they are readily involved in the activation of resting NK cells (5), a reduced display of constitutively expressed activating receptors, such as NKG2D, NKp30, NKp46, DNAM-1, and 2B4, may dampen the functional capacity of NK cells to fight against viral infection. Cytokines secreted in response to HCMV infection indeed inhibit NKG2D expression on the surface of NK cells and limit the ability of NK cells to exert cytotoxicity against target cells (25).The prominent role of NK cells in the innate immune response to virus infection has prompted studies of the NK cell phenotype and functional properties in HCV infection. These include in vitro studies using HCV replicon systems, expression vectors encoding HCV proteins, and recombinant HCV proteins (9,12,24,35,36). For various reasons, these studies yielded contradictory results (12,24,35). It is difficult to interpret interaction between NK cells and HCV-infected cells in noninfectious models, which do not completely simulate the natural life cycle of HCV (19). Ex vivo studies using peripheral blood mononuclear cells (PBMCs) from patients with hepatitis C also showed discrepancies in the functional status of NK cells in HCV infection (1,11,15,26,27,30).Though small-animal models for immunologic research are not readily available yet, recently developed cell culture systems that generate infectious HCV virions in vitro provide more physiological settings in which to study interaction be-* Corresponding author. Mailing address:

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“…In contrast, as reported previously, administration of a combination of IL-2 + IL-12 enhanced IFNγ production in NK cells (fig. 3A-C) [25,26]. Surprisingly, coadministration of TNFα, or a TNFR2 agonistic antibody, to NK cells that were also treated with IL-2 + IL-12 resulted in a synergistic augmentation of IFNγ production (fig.…”

Section: Resultsmentioning

confidence: 99%

“…To stimulate submaximal IFNγ production from NK cells, cells were treated with IL-2 and IL-12 (each 20 ng/ml) for 24 h (concentrations were determined in pilot experiments and are consistent with those in previous reports) [25,26]. For FACS (fluorescence-activated cell sorting) analyses, medium was supplemented with protein transport inhibitors (brefeldin A and monensin at 3.0 µg/ml and 2 m M , respectively, for the last 5 h of incubation).…”

Section: Methodsmentioning

confidence: 99%

TNFα Augments Cytokine-Induced NK Cell IFNγ Production through TNFR2

Almishri

Santodomingo-Garzón

et al. 2016

J Innate Immun

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NK cells play a central role in innate immunity, acting directly through cell-mediated cytotoxicity and by secreting cytokines. TNFα activation of TNFR2 enhances NK cell cytotoxicity, but its effects on the other essential function of NK cells - cytokine production, for which IFNγ is paramount - are poorly defined. We identify the expression of both TNFα receptors on human peripheral blood NK cells (TNFR2 > TNFR1) and show that TNFα significantly augments IFNγ production from IL-2-/IL-12-treated NK cells in vitro, an effect mimicked by a TNFR2 agonistic antibody. TNFα also enhanced murine NK cell IFNγ production via TNFR2 in vitro. In a mouse model characterized by the hepatic recruitment and activation of NK cells, TNFR2 also regulated NK cell IFNγ production in vivo. Specifically, in this model, after activation of an innate immune response, hepatic numbers of TNFR2-expressing and IFNγ-producing NK cells were both significantly increased; however, the frequency of IFNγ-producing hepatic NK cells was significantly reduced in TNFR2-deficient mice. We delineate an important role for TNFα, acting through TNFR2, in augmenting cytokine-induced NK cell IFNγ production in vivo and in vitro, an effect with significant potential implications for the regulation of innate and adaptive immune responses.

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Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection

Cited by 72 publications

References 33 publications

Control of the HIV-1 DNA Reservoir Is AssociatedIn VivoandIn Vitrowith NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

Control of the HIV-1 DNA Reservoir Is AssociatedIn VivoandIn Vitrowith NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

Cell-to-Cell Contact with Hepatitis C Virus-Infected Cells Reduces Functional Capacity of Natural Killer Cells

TNFα Augments Cytokine-Induced NK Cell IFNγ Production through TNFR2

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Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection

Cited by 72 publications

References 33 publications

Control of the HIV-1 DNA Reservoir Is AssociatedIn VivoandIn Vitrowith NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

Control of the HIV-1 DNA Reservoir Is AssociatedIn VivoandIn Vitrowith NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

Cell-to-Cell Contact with Hepatitis C Virus-Infected Cells Reduces Functional Capacity of Natural Killer Cells

TNFα Augments Cytokine-Induced NK Cell IFN&#x03B3; Production through TNFR2

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TNFα Augments Cytokine-Induced NK Cell IFNγ Production through TNFR2