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 AND 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-lambdaR 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-lambdaR) 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-lambdaR 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-lambdaR 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 anti-inflammatory and/or anti-viral potential of IFN-lambda in cHCV