Natural killer cells: Multifaceted players with key roles in hepatitis C immunity

Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver (UCD), Aurora, CO, USA
Immunological Reviews (Impact Factor: 10.12). 09/2013; 255(1):68-81. DOI: 10.1111/imr.12090
Source: PubMed


Natural killer cells (NKs) are involved in every stage of hepatitis C viral (HCV) infection, from protection against HCV acquisition and resolution in the acute phase to treatment-induced clearance. In addition to their direct antiviral actions, NKs are involved in the induction and priming of appropriate downstream T-cell responses. In the setting of chronic HCV, overall NK cell levels are decreased, subset distribution is altered, and changes in NK receptor (NKR) expression have been demonstrated, although the contribution of individual NKRs to viral clearance or persistence remains to be clarified. Enhanced NK cell cytotoxicity accompanied by insufficient interferon-γ production may promote liver damage in the setting of chronic infection. Treatment-induced clearance is associated with activation of NK cells, and it will be of interest to monitor NK cell responses to triple therapy. Activated NK cells also have anti-fibrotic properties, and the same hepatic NK cell populations that are actively involved in control of HCV may also be involved in control of HCV-associated liver damage. We still have much to learn, in particular: how do liver-derived NKs influence the outcome of HCV infection? Do NK receptors recognize HCV-specific components? And, are HCV-specific memory NK populations generated?


Available from: Lucy Golden-Mason
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    • "The control of NK cell activity is dependent on membrane-expressed inhibitory NK receptors (NKRs), which in steady-state conditions override signals provided by engagement of activating receptors [24] [25] [26]. Recent studies have highlighted important roles for NK cells in immunity against hepatotrophic viruses including HCV [27]. Overall, data suggest that defective NK cell responses contribute to chronic HCV persistence and failure to respond to IFN-α-based therapy whereas restoration of NK cell function contributes to successful viral control [28] [29] [30] [31] [32] [33] [34] [35]. "
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    ABSTRACT: T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is an inhibitory receptor implicated in T cell exhaustion characteristic of chronic viral infection. Limited data exist on NK cell Tim-3 expression and functional consequences. In chronic hepatitis C virus (HCV) infected subjects, we found increased Tim-3 on NKs which was associated with an activated phenotype. The high level of Tim-3 was not reversed by successful IFN-alpha based anti-viral therapy. Tim-3(high) NK cells up-regulated TRAIL in response to IFN-alpha to a greater extent and demonstrated greater lymphokine-activated killing activity, viral control and degranulation but similar cytokine production than their Tim-3(low) counterparts. Our results suggest that Tim-3 on NKs is associated with activation of this innate lymphocyte population that is polarized towards cytotoxicity in chronic HCV. These findings reveal roles for Tim-3 in the regulation of NKs that might represent targets for treatment of chronic viral infections. Copyright © 2015. Published by Elsevier Inc.
    Clinical Immunology 03/2015; 158(1). DOI:10.1016/j.clim.2015.03.008 · 3.67 Impact Factor
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    • "HCV infection is controlled by both innate and adaptive immunity [3] [4]. Natural killer (NK) cells are important element of innate immunity against viruses, although their numbers decrease in the liver during chronic HCV infection [5] [6]. These numbers, however , are increased again in hepatocellular carcinoma patients [7]. "
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    ABSTRACT: Natural killer (NK) cells are an important element of innate immunity against viruses, although their numbers decrease in the liver during chronic HCV infection. NK cells express a large panel of inhibitory and activating receptors. The most polymorphic of these are killer cell immunoglobulin-like receptors (KIRs) which are encoded by multiple genes that may be present or absent in given individuals depending on their genotype. This variability results in differential susceptibility to viral infections and diseases, including HCV infection and its consequences. The aim of this study was to test whether chronical infection with HCV and the viremia levels are associated with any KIR gene in the Polish population. We typed 301 chronically HCV-infected patients and 425 non-infected healthy individuals for the presence or absence of KIR genes and their ligands, HLA-C C1 and C2 groups as well as HLA-B and HLA-A Bw4-positive alleles. We found that males, but not females, possessing KIR2DS2 and KIR2DL2 genes had a 1.7 higher probability to become chronically HCV-infected than males negative for these genes (p = 0.0213). In accord with this, centromeric B region, containing KIR2DS2 and KIR2DL2 genes, was also associated with chronic HCV infection in males. In addition, patients of both genders possessing KIR2DS3 but not KIR2DS5 gene exhibited, on average, 2.6 lower level of viremia than HCV-infected individuals with other genotypes (p = 0.00282). This was evident in those infected at a young age. KIR2DS3-positive patients also had lower mean levels of bilirubin than KIR2DS3-negative ones (p = 0.02862). Our results suggest a contribution of the KIR2DS2 and KIR2DL2 genes (cenB haplotype) to the susceptibility to chronic HCV infection, and an association of the KIR2DS3 gene in the absence of KIR2DS5 with low viremia levels. Copyright © 2015. Published by Elsevier Inc.
    Human Immunology 01/2015; 76(2-3). DOI:10.1016/j.humimm.2015.01.020 · 2.14 Impact Factor
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    • "Natural killer (NK) cells provide a major component of the innate antiviral immune response through recognition and killing of virally infected cells and induction of appropriate T cell responses [5]–[7] [8], [9]. Recent studies have highlighted important roles for NK cells in immunity against hepatotrophic viruses including HCV [10]. Several studies suggest that defective NK cell responses contribute to chronic HCV persistence [11]–[18]. "
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    ABSTRACT: Background: Hepatitis C viral (HCV) proteins, including core, demonstrate immuno-modulatory properties; however, the effect of extracellular core on natural killer (NK) cells has not previously been investigated. Aims: To characterise NKs in acute HCV infection over time, and, to examine the effect of exogenous HCV-core protein on NK cell phenotype and function. Methods: Acute HCV patients (n = 22), including 10 subjects who spontaneously recovered, were prospectively studied. Flow-cytometry was used to measure natural cytotoxicity and to phenotype NKs directly ex vivo and after culture with HCV-core protein. Microarray analysis was used to identify pathways involved in the NK cell response to exogenous HCV-core. Results: Direct ex vivo analysis demonstrated an increased frequency of immature/regulatory CD56(bright) NKs early in acute HCV infection per se which normalized with viral clearance. Natural cytotoxicity was reduced and did not recover after viral clearance. There was a statistically significant correlation between the frequency of CD56(bright) NKs and circulating serum levels of HCV core protein. In vitro culture of purified CD56(bright) NK cells with HCV-core protein in the presence of IL-15 maintained a significant proportion of NKs in the CD56(bright) state. The in vitro effect of core closely correlates with NK characteristics measured directly ex vivo in acute HCV infection. Pathway analysis suggests that HCV-core protein attenuates NK interferon type I responses. Conclusions: Our data suggest that HCV-core protein alters NK cell maturation and may influence the outcome of acute infection.
    PLoS ONE 07/2014; 9(7):e103219. DOI:10.1371/journal.pone.0103219 · 3.23 Impact Factor
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