Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection

Research Laboratories Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
Hepatology (Impact Factor: 11.06). 09/2012; 56(3):841-9. DOI: 10.1002/hep.25723
Source: PubMed


Hepatitis C virus (HCV) persistence in the host results from inefficiencies of innate and adaptive immune responses. Most studies addressing the role of innate immunity concentrated on peripheral blood (PB) natural killer (NK) cells, whereas only limited information is available on intrahepatic (IH) NK cells. We therefore examined phenotypic and functional features of IH and PB NK cells in paired liver biopsy and venous blood samples from 70 patients with chronic HCV infection and 26 control persons subjected to cholecystectomy for gallstones as controls. Ex vivo isolated IH NK cells from HCV-infected patients displayed unique phenotypic features, including increased expression of NKp46-activating receptor in the face of reduced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cluster of differentiation (CD) 107a expression, which resulted in impaired degranulation compared with controls. To gain insights into the effect of HCV on NK cells, we exposed peripheral blood mononuclear cells (PBMCs) from patients and healthy donors to cell-culture-derived HCV (HCVcc) and measured NK cell degranulation, TRAIL, and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression. Exposure of PBMCs to HCVcc significantly boosted NK degranulation, pERK1/2, and TRAIL expression in healthy donors, but not in patients with chronic HCV infection, a defect that was completely reversed by interferon-alpha. Purified NK cells showed a minimal, though significant, increase in degranulation and TRAIL expression, both in patients and controls, after exposure to HCVcc. CONCLUSIONS: These findings indicate dysfunctional IH NK cell cytotoxicity associated with TRAIL down-regulation in chronic HCV infection, which may contribute to virus persistence. PB NK cell impairment upon exposure to HCVcc suggests the existence of an accessory cell-dependent NK cell lytic defect in chronic HCV infection predominantly involving the TRAIL pathway.

Download full-text


Available from: Mario U Mondelli, Oct 10, 2015
39 Reads
  • Source
    • "It is known that the TRAIL level is significantly higher in patients with CHC [23] [24]. Because TRAIL is a defense mechanism to eliminate infected hepatocytes. "
    [Show abstract] [Hide abstract]
    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.
    International Journal of Clinical and Experimental Medicine 12/2014; 7(12). · 1.28 Impact Factor
  • Source
    • "These results suggest that although HCV E2 may specifically bind to CD81 on NK cells, the configuration of E2 within an intact infectious virus particle does not facilitate the degree of NK CD81 receptor cross-linking necessary to mediate an inhibitory signal [97, 98]. Most of these systems used peripheral NK cells stimulated in vitro with recombinant IL-2 (rIL-2), rIL-12, or IFN-α combined with extended coculture with HCV-infected cells, introducing additional complications to interpreting in vivo relevance of the reported effects [67, 68, 97, 98, 104]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Viruses must continually adapt against dynamic innate and adaptive responses of the host immune system to establish chronic infection. Only a small minority (~20%) of those exposed to hepatitis C virus (HCV) spontaneously clear infection, leaving approximately 200 million people worldwide chronically infected with HCV. A number of recent research studies suggest that establishment and maintenance of chronic HCV infection involve natural killer (NK) cell dysfunction. This relationship is illustrated in vitro by disruption of typical NK cell responses including both cell-mediated cytotoxicity and cytokine production. Expression of a number of activating NK cell receptors in vivo is also affected in chronic HCV infection. Thus, direct in vivo and in vitro evidence of compromised NK function in chronic HCV infection in conjunction with significant epidemiological associations between the outcome of HCV infection and certain combinations of NK cell regulatory receptor and class I human histocompatibility linked antigen (HLA) genotypes indicate that NK cells are important in the immune response against HCV infection. In this review, we highlight evidence suggesting that selective impairment of NK cell activity is related to establishment of chronic HCV infection.
    BioMed Research International 06/2014; 2014(1):903764. DOI:10.1155/2014/903764 · 2.71 Impact Factor
  • Source
    • "Cells were then harvested, washed and stained for flow cytometric analysis. Degranulation activity was monitored by detection of membranous presence of CD107a marker [12], [14], [15], [32]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During chronic hepatitis C virus (HCV) infection, the role of intra-hepatic (IH) natural killer (NK) cells is still controversial. To clarify their functions, we investigated anti-viral and cytotoxic activity of NK cells in human fresh liver biopsies. We compared the functions of IH-NK cells in HCV-infected and NASH patients in physiological conditions as well as after stimulation using flow cytometric and immunohistochemical analyses. Interestingly, few IH-NK cells produced anti-viral cytokine IFN-γ in HCV-infected patients similarly as in non-infected individuals. Spontaneous degranulation activity was extremely low in peripheral NK cells compared to IH-NK cells, and was significantly higher in IH-NK cells from HCV-infected patients compared to non-infected individuals. Immunohistochemical analysis revealed that perforin granules were polarized at the apical pole of IH-NK cells. The presence of CD107a and perforin in IH-NK cells demonstrated that NK cells exerted a cytolytic activity at the site of infection. Importantly, IH-NK cell functions from HCV-infected patients were inducible by specific exogenous stimulations. Upon ex vivo K562 target cell stimulations, the number of degranulating NK cells was significantly increased in the pool of IH-NK cells compared to circulating NK cells. Interestingly, after stimulation, the frequency of IFN-γ-producing IH-NK cells in HCV-infected patients was significantly higher at early stage of inflammation whereas the spontaneous IH-NK cell degranulation activity was significantly impaired in patients with highest inflammation and fibrosis Metavir scores. Our study highlights that some IH-NK cells in HCV-infected patients are able to produce INF-γ and degranulate and that those two activities depend on liver environment including the severity of liver injury. Thus, we conclude that critical roles of IH-NK cells have to be taken into account in the course of the liver pathogenesis associated to chronic HCV infection.
    PLoS ONE 04/2014; 9(4):e95614. DOI:10.1371/journal.pone.0095614 · 3.23 Impact Factor
Show more