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Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection
Author(s) -
Varchetta Stefania,
Mele Dalila,
Mantovani Stefania,
Oliviero Barbara,
Cremonesi Eleonora,
Ludovisi Serena,
Michelone Giuseppe,
Alessiani Mario,
Rosati Riccardo,
Montorsi Marco,
Mondelli Mario U.
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25723
Subject(s) - degranulation , immunology , biology , peripheral blood mononuclear cell , lymphokine activated killer cell , innate immune system , immune system , natural killer cell , interleukin 21 , nkg2d , cytotoxic t cell , hepatitis c virus , cd8 , virus , receptor , in vitro , biochemistry
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. (H EPATOLOGY 2012;56:841–849)