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.

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    • "While liver samples from patients with chronic HCV are relatively easier to come by, it is substantially more difficult to get liver samples from healthy controls, and our knowledge of events in the liver is relatively poor compared to information on systemic immune events during HCV infection. 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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    • "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. "
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    • "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]. "
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