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 tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD107a 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 (PBMC) from patients and healthy donors to culture-derived HCV (HCVcc) and measured NK cell degranulation, TRAIL and phosphorylated ERK1/2 expression. Exposure of PBMC to HCVcc significantly boosted NK degranulation, ERK1/2 phosphorylation and TRAIL expression in healthy donors but not in patients with chronic HCV infection, a defect that was completely reversed by interferon-α. 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 downregulation 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.).
Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection
M. Montorsi;
2012-01-01
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 tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD107a 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 (PBMC) from patients and healthy donors to culture-derived HCV (HCVcc) and measured NK cell degranulation, TRAIL and phosphorylated ERK1/2 expression. Exposure of PBMC to HCVcc significantly boosted NK degranulation, ERK1/2 phosphorylation and TRAIL expression in healthy donors but not in patients with chronic HCV infection, a defect that was completely reversed by interferon-α. 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 downregulation 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.).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
