Abstract
BackgroundImmuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity.MethodsA total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both. NK cell IFN-γ response was analysed by FACS. IL-12 and IL-18 secretion of monocytes was studied by ELISA. In blocking experiments anti-IL-12/anti-IL-18 were used.ResultsFollowing stimulation of total PBMCs with R848 we found NK cell IFN- γ responses to vary with the IL-28B genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-γ(+)NK cells. When isolated NK cells were studied no such associations were observed, indicating an indirect association between IL-28B genotype and NK cell activity. Accordingly, we found R848-stimulated monocytes of patients with a T/T genotype to be significantly less effective in triggering NK cell IFN- γ production than monocytes from carriers of a non-T/T genotype. In line with these findings we observed monocytes from T/T patients to secrete significantly lower concentrations of IL-12 than monocytes from non-T/T individuals.ConclusionsOur data indicate that monocytes from carriers of an IL-28B T/T genotype display a reduced ability to stimulate NK cell activity and, thus, provide a link between IL-28B genotype and NK functions.
Highlights
Infection with the hepatitis C virus (HCV) is a major cause of blood-borne hepatitis worldwide
Following stimulation of total Peripheral blood mononuclear cells (PBMC) with R848 we found natural killer (NK) cell IFN- γ responses to vary with the interleukin 28 B (IL-28B) genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-γ(+)NK cells
Our data indicate that monocytes from carriers of an IL-28B T/T genotype display a reduced ability to stimulate NK cell activity and, provide a link between IL-28B genotype and NK functions
Summary
Infection with the hepatitis C virus (HCV) is a major cause of blood-borne hepatitis worldwide. Numerous genetic variants have been proposed to be associated with spontaneous and/or treatment-induced clearance of HCV infection. Prokunina-Olsson et al identified a genetic variant rs368234815 (TT or ΔG) upstream of the IFNL3 gene, which creates (ΔG) or disrupts (TT) an open reading frame in a new gene, designated IFNL4 [6]. This polymorphism is in high linkage disequilibrium with rs12979860 and was found to be more strongly associated with HCV clearance than the IL28B rs12979860 variant in individuals of African ancestry, but to provide comparable information in Europeans and Asians. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have