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

TY - JOUR

T1 - Altered effector functions of NK cells in chronic hepatitis c are associated with IFNL3 polymorphism

AU - Rogalska-Taranta, Magdalena

AU - Markova, Antoaneta A.

AU - Taranta, Andrzej

AU - Lunemann, Sebastian

AU - Schlaphoff, Verena

AU - Flisiak, Robert

AU - Manns, Michael P.

AU - Cornberg, Markus

AU - Kraft, Anke R.M.

AU - Wedemeyer, Heiner

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

KW - Cytotoxicity

KW - HCV

KW - IFN-α

KW - IFN-γ

KW - STATs

KW - TRAIL

UR - http://www.scopus.com/inward/record.url?scp=84938299921&partnerID=8YFLogxK

U2 - 10.1189/jlb.4a1014-520r

DO - 10.1189/jlb.4a1014-520r

M3 - Journal article

C2 - 26034208

AN - SCOPUS:84938299921

SN - 0741-5400

VL - 98

SP - 283

EP - 294

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

IS - 2

ER -