Intrahepatic natural killer cell NKp46 expression drives HCV-associated liver inflammation and viral resistance to treatment with interferon alpha

Abstract

BackgroundThere is evidence that natural killer (NK) cells help control persistent viral infections including hepatitis C virus (HCV). HCV infection is treated with interferon (IFN) alpha, which stimulates the immune system, and is successful in 40–80% of patients. Detailed comparison of the phenotype and function of blood and intrahepatic NK cells in chronic HCV infection and in response to treatment with IFN alpha has not been elucidated. MethodsWe performed a comparison of NK cells derived from blood and intrahepatic compartments in multiple paired samples from 24 HCV infected patients pretreatment and 22 patients with non-viral chronic liver disease (CLD). NK phenotype (CD16, NKp30, NKp46, NKG2D, and NKG2A) and functional profile (CD107a, IFNγ, and granzyme B) were assessed with flow cytometry. In a separate cohort of 17 patients with HCV, who had completed treatment, rate of viral clearance was calculated and pretreatment peripheral blood NK phenotype and CD107a expression (degranulation) in response to increasing stimulation was measured. FindingsNK cells in the liver demonstrate a distinct phenotype compared with blood, manifested as downregulation of the NK cell activation receptors CD16, NKG2D, and NKp30. By contrast, NKp46 expression was not downregulated. Intrahepatic NK cells appeared to be more activated with increased spontaneous degranulation (reduced granzyme B, p<0·001 and increased CD107a, p=0·006) and production of IFNγ (p=0·05). NKp46 expression correlated with NK-cell activation, and correlated closely with the severity of liver inflammation (p=0·035). The rate of viral clearance during treatment with IFN alpha inversely correlated with NKp46 expression at baseline (p=0·01). However, the ability to increase cytotoxic NK function in response to increasing stimulation ex vivo correlated with viral clearance (p=0·029) and inversely with NKp46 (p=0·005). InterpretationThese findings indicate that NKp46 marks out pathologically activated NK cells in HCV, which are unlikely to be involved in viral control in IFN alpha-treated individuals. FundingWelsh Assembly.