Type III interferons, IL-28 and IL-29, are increased in chronic HCV infection and induce myeloid dendritic cell-mediated FoxP3+ regulatory T cells.

ABSTRACT:

Background & aims

Hepatitis C virus (HCV) is difficult to eradicate and type III interferons (IFN-?, composed of IL-28A, IL-28B and IL-29) are novel therapeutic candidates. We hypothesized that IFN-? have immunomodulatory effects in HCV- infected individuals.

Materials and methods

We analyzed the expression of IFN-? and its receptor (composed of IL-10R2 and IFN-?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-? receptor (IFN-?R) on myeloid DCs, plasmacytoid DCs, PBMCs, and T cells was determined by FACS analysis.

Results

We report that the expression of IFN-? 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-?R mirrored the expression of serum IFN-? and was higher in cHCV, compared to controls and HCV-SVR patients, suggesting that elevation of IFN-? and IFN-?R are HCV-dependent. We further identified that innate immune cell populations expressed complete IFN-? receptor. In vitro, recombinant IFN-? 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-?-DCs failed to induce de novo generation of regulatory T cells. The inhibitory capacity of IFN-?-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-? contribute to the understanding of the anti-inflammatory and/or anti-viral potential of IFN-? in cHCV.

SUBMITTER: Dolganiuc A 

PROVIDER: S-EPMC3468613 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature