Natural Killer Cells Are Polarized Toward Cytotoxicity in Chronic Hepatitis C in an Interferon-Alfa–Dependent Manner

Immunology Section, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-1800, USA.
Gastroenterology (Impact Factor: 16.72). 09/2009; 138(1):325-35.e1-2. DOI: 10.1053/j.gastro.2009.08.066
Source: PubMed


Patients with chronic hepatitis C virus (HCV) infection display great variability in disease activity and progression. Although virus-specific adaptive immune responses have been characterized extensively and found to be impaired in chronic hepatitis C, the role of innate immune responses in disease activity and progression of chronic hepatitis C is not well understood.
We studied 42 HCV-infected patients and 12 healthy uninfected controls.
We found an increased frequency of natural killer (NK) cells expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), NKp44, NKG2C, and CD122 in chronic hepatitis C as compared with healthy controls (P < .05 for all markers) and stronger activation of NK cells in the liver than in the blood (P < .05). This NK cell phenotype was associated with polarization of NK cell function toward CD107a expression as a marker of degranulation, but with not increased interferon (IFN)-gamma production of CD56(dim) NK cells. The polarized NK cell phenotype correlated with alanine aminotransferase levels (r(2) = 0.312, P = .03). To investigate whether in vivo exposure of NK cells to HCV-induced type I IFN was causing this NK cell phenotype, peripheral blood mononuclear cells from 10 healthy controls and 8 HCV-infected patients were stimulated in the presence of IFN-alfa, which resulted in increased NK cell expression of TRAIL and CD107a (P < .001), but not IFN-gamma.
Collectively, these results describe a polarized NK cell phenotype induced by chronic exposure to HCV-induced IFN-alfa. This phenotype may contribute to liver injury through TRAIL expression and cytotoxicity, whereas the lacking increase in IFN-gamma production may facilitate the inability to clear HCV.

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    • "The limited data available suggest that differences exist between matched peripheral blood and hepatic NK cells in terms of phenotype and function, and that differences are also seen between hepatic NK cells of patients with chronic HCV compared with controls (Kawarabayashi et al., 2000; Varchetta et al., 2012). Despite this caveat, there are clear changes in systemic immune cells during infection and there is some evidence that changes observed in the periphery are similar to those seen in liver albeit with relatively lower levels of magnitude (Ahlenstiel et al., 2010). "
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    ABSTRACT: Hepatitis C virus (HCV) infects over 170 million people in the world. While a minority of individuals are able to naturally clear this hepatotropic virus using their immune system, most people go on to develop a lifetime chronic infection that can result in severe liver pathology, potentially leading to liver cirrhosis and hepatic cellular carcinoma. Investigations into acute immune responses and spontaneous clearance of the virus are severely hampered by difficulties in identification of relevant patient cohorts. While the role for the adaptive immune response in viral clearance is well established, it is becoming clear that the innate immune system also impacts on HCV outcome. The innate immune response to infection is likely to influence the type of adaptive immune response that develops and will ultimately influence if the virus is cleared or develops into a chronic infection. Natural Killer (NK) cells are lymphocytes that have important anti-viral functions including direct cytotoxicity of infected cells and the production of inflammatory cytokines, e.g., IFN-γ. They are generally considered to be cells of the innate immune system, although there is increasing evidence that NK cells adapt and persist in response to particular viral infections. NK cells are altered in patients with acute and chronic HCV infection. There is increasing evidence from both cellular and genetic studies that NK cells modulate HCV outcome. This review will describe and discuss the current experimental and clinical evidence of a role for NK cells in HCV infection and describe recent discoveries that are likely to play a role in future research.
    Full-text · Article · Sep 2015 · Frontiers in Microbiology
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    • "Recently, a subpopulation of highly differentiated NK cells of CD56 dim CD57 + NKG2C + phenotype, expressing self-HLA-class-Ispecific inhibitory KIRs, was described to expand in chronically HCV-infected patients [34] [35], but only if they were human cytomegalovirus (HCMV)-positive [36]. This latter finding is not surprising , as NK cells with this phenotype were expanding also in response to HCMV infection alone, without HCV co-infection [37] [38]. "
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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.
    Preview · Article · Jan 2015 · Human Immunology
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    • "When NK cells are activated in chronically HCV-infected patients, they exhibit a polarized phenotype with increased TRAIL expression and degranulation , but not IFNγ. Consequently, IFNγmediated viral clearance is more effective than elimination of virus-infected hepatocytes by cytotoxic mechanisms [12]. Stegmann et al. also showed that IFNα induced TRAIL has a highly functional role and contributed to elimination of infected hepatocytes in CHC infection [16]. "
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    ABSTRACT: The molecular mechanisms and pathogenesis of chronic hepatitis C (CHC) infection are unclear. Innate immune cells such as natural killer (NK) cells and dendritic cells are responsible from molecular mechanism of CHC. NK cell cytotoxicity such as TRAIL expression is important pathway for viral clearance. The aim of this study was to evaluate the relationship between HCV RNA and sTRAIL levels during the first 12 weeks of Peg-IFNα and ribavirin treatment. Twelve treatment naive patients with CHC treated with Peg-INFα and ribavirin were included in this study. Circulating sTRAIL and HCV RNA levels were measured at baseline, 4th and 12th week of treatment and their correlation was investigated. sTRAIL and HCV RNA levels decreased gradually with Peg-INFα plus ribavirin treatment. The differences were significant between day 0, 4th week and 12th week of treatment. The expression of sTRAIL was correlated with HCV RNA level at baseline, at 4th and 12th week of treatment (P = 0.021 P = 0.012, P = 0.001 respectively). IFN binds to its receptor on the infected hepatocyte surface during Peg-IFNα and ribavirin treatment. So the polarized phenotype of NK cell is not displayed and NK cell cytotoxicity such as TRAIL expression is blocked. We suggest that the decreased level of circulating sTRAIL may reflect increased binding to its ligand expressed on hepatocyte and decreased TRAIL production under the influence of Peg-IFNα plus ribavirin treatment. Therefore TRAIL may be probably a immunologically predictive factor such as HCV RNA during treatment.
    Full-text · Article · Dec 2014 · International Journal of Clinical and Experimental Medicine
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