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

Background & Aims: Hepatitis C virus (HCV) is difficult to eradicate and type III interferons (IFN-lambda, composed of IL-28A, IL-28B and IL-29) are novel therapeutic candidates. We hypothesized that IFN-lambda have immunomodulatory effects in HCV-infected individuals. Materials and Methods: We analyzed the expression of IFN-lambda and its receptor (composed of IL-10R2 and IFN-lambda R 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-lambda receptor (IFN-lambda R) on myeloid DCs, plasmacytoid DCs, PBMCs, and T cells was determined by FACS analysis. Results: We report that the expression of IFN-lambda 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-lambda R mirrored the expression of serum IFN-lambda and was higher in cHCV, compared to controls and HCV-SVR patients, suggesting that elevation of IFN-lambda and IFN-lambda R are HCV-dependent. We further identified that innate immune cell populations expressed complete IFN-lambda receptor. In vitro, recombinant IFN-lambda promoted differentiation of monocyte-derived dendritic cells (DCs) into a phenotype with low T cell stimulatory capacity and high PD-L1 expression, which further promoted expansion of existing regulatory T cells. IFN-lambda-DCs failed to induce de novo generation of regulatory T cells. The inhibitory capacity of IFN-lambda-DCs was counteracted by recombinant IL-12 and by neutralization of the PD-1/PD-L1 system. Conclusions: Our novel findings of the immunomodulatory effect of IFN-lambda contribute to the understanding of the antiinflammatory and/or anti-viral potential of IFN-lambda in cHCV.