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

Abstract

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. (HEPATOLOGY 2012;56:841–849)

Hepatitis C Virus Impairs Natural Killer Cell-Mediated Augmentation of Complement Synthesis

“…NKG2D is a relatively conserved protein on NK cells, the function of which appears to be important for C3/C4 recovery as indicated by our observations. Its interaction with MICA/B is also well defined in the literature (30) and is the mechanism which we now believe to be relevant in C3/C4 synthesis and modulation in the face of added NK cell-mediated immune modulation.…”

“…NK cells may directly target HCV-infected hepatocytes or indirectly influence immune cells, such as dendritic cells (DCs) or T cells for viral clearance. Perturbations in NK cell frequency, phenotype, and function have been shown in chronically HCV-infected patients (30). The peripheral blood NK cell number and percentage of total lymphocyte population are lower in HCV-infected individuals (8).…”

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

“…81 Notably, persistent HBV or HCV infection, which is the main risk factor for HCC, has been shown to influence NK cell phenotype, especially by increasing expression of inhibitory receptors and reducing expression of activating receptors (Table 3). [82][83][84][85][86][87][88][89] In one study, NK cells from chronic HCV patients had a significantly reduced expression of NKp46 and NKp30 and an increased expression of NKG2A compared with NK cells from healthy and HBV infected subjects. 88 Our group recently found a higher percentage of NKG2A 1 NK cells in peripheral blood from patients with active CHB patients than from patients with inactive CHB or from control patients.…”

Quantitative Effect of Natural Killer–Cell Licensing on Hepatocellular Carcinoma Recurrence after Curative Hepatectomy

“…Taken together, with this finding and the fact that the number and type of host MHC class I alleles quantitatively tune the responsiveness of individual NK-cell subsets expressing the corresponding KIR (14,22), the effect of NK-cell licensing on HCC recurrence should be quantitative. This effect of NK-cell licensing on HCC recurrence reached statistical significance in the non-HCV-related cohort but not in the HCV-related cohort, which might be explained by the fact that hepatic NK cells exhibited reduced cytotoxicity and TRAIL expression in patients with chronic HCV infection (23).…”