Altered effector functions of NK cells in chronic hepatitis C are associated with IFNL3 polymorphism

• Published in: Journal of leukocyte biology Vol. 98; no. 2; pp. 283 - 294
• Main Authors: Rogalska‐Taranta, Magdalena, Markova, Antoaneta A., Taranta, Andrzej, Lunemann, Sebastian, Schlaphoff, Verena, Flisiak, Robert, Manns, Michael P., Cornberg, Markus, Kraft, Anke R. M., Wedemeyer, Heiner
• Format: Journal Article
• Language: English
• Published: England 01.08.2015
• Subjects: Adult; Aged; Alleles; Antiviral Agents - therapeutic use; Case-Control Studies; cytotoxicity; Female; Gene Expression Regulation; Genotype; HCV; Hepatitis C - immunology; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - pathology; Humans; IFN‐α; IFN‐γ; Interferon-alpha - therapeutic use; Interferons; Interleukins - genetics; Interleukins - immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Killer Cells, Natural - virology; Liver - immunology; Liver - pathology; Liver - virology; Male; Middle Aged; Polymorphism, Single Nucleotide; Signal Transduction; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - immunology; STAT4 Transcription Factor - genetics; STAT4 Transcription Factor - immunology; STATs; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - immunology; TRAIL; Viral Load - immunology; IFN-α; IFN-γ; HCV; TRAIL; cytotoxicity; STATs
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.4A1014-520R

IFNL3 polymorphism differentially influences NK cell functions upon IFN‐α stimulation; the role of NK cells may differ in chronic infection vs. early antiviral defense. Interferon α‐mediated effector functions of NK cells may contribute to the control of HCV replication and the pathogenesis of liver disease. The single‐nucleotide polymorphism rs12979860 near IFNL3 (previously known as IL28B) is important in response to IFN‐α treatment and in spontaneous resolution of acute hepatitis C. The role of the IFNL3 polymorphism in NK cell function is unclear. Thus, we investigated the role of IFNL3 polymorphism in type I IFN‐dependent regulation of NK cell functions in patients with cHC and healthy control subjects. We demonstrated a marked polarization of NK cells toward cytotoxicity in response to IFN‐α stimulation in patients with hepatitis C. That TRAIL up‐regulation was present, particularly in patients with the IFNL3‐TT allele, was supported by a shift in the pSTAT‐1:pSTAT‐4 ratios toward pSTAT‐1. In patients bearing the IFNL3‐TT allele, NK cell effector function correlated with liver disease activity. In contrast, higher cytokine production of NK cells was observed in healthy individuals with the IFNL3‐CC genotype, which may support spontaneous HCV clearance in acute infection. Overall, these findings show that the role of NK cells may differ in chronic infection vs. early antiviral defense and that the IFNL3 genotype differentially influences NK cell function.