Type III Interferons, IL-28 and IL-29, Are Increased in Chronic HCV Infection and Induce Myeloid Dendritic Cell- Mediated FoxP3+ Regulatory

Background & Aims: Hepatitis C virus (HCV) is difficult to eradicate and type III interferons (IFN-l, composed of IL-28A, IL-28B and IL-29) are novel therapeutic candidates. We hypothesized that IFN-l have immunomodulatory effects in HCV-infected individuals. Materials and Methods: We analyzed the expression of IFN-l and its receptor (composed of IL-10R2 and IFN-lR subunits) in the blood and livers of patients with chronic (c)HCV infection compared to controls (those who cleared HCV by sustained virological response, SVR, and those with liver inflammation of non-viral origin, non-alcoholic steatohepatitis, NASH). We also compared the proliferative capacity of dendritic cells (DCs) obtained from healthy individuals and those with chronic HCV using a mixed leukocyte reaction combined with 3H-Td incorporation. In addition, the composition of the IFN-l receptor (IFN-lR) on myeloid DCs, plasmacytoid DCs, PBMCs, and T cells was determined by FACS analysis. Results: We report that the expression of IFN-l protein in serum and mRNA in liver is increased in cHCV patients, but not in those with HCV SVR or NASH, compared to controls. Liver level of IFN-lR mirrored the expression of serum IFN-l and was higher in cHCV, compared to controls and HCV-SVR patients, suggesting that elevation of IFN-l and IFN-lR are HCV-dependent. We further identified that innate immune cell populations expressed complete IFN-l receptor. In vitro, recombinant IFN-l promoted differentiation of monocyte-derived dendritic cells (DCs) into a phenotype with low T cel