Type III interferons, IL-28 and IL-29, are increased in chronic HCV infection and induce myeloid dendritic cell-mediated FoxP3+ regulatory T cells.
OBJECTIVE
Hepatitis C virus (HCV) is difficult to eradicate and type III interferons (IFN-λ, composed of IL-28A, IL-28B and IL-29) are novel therapeutic candidates. We hypothesized that IFN-λ have immunomodulatory effects in HCV- infected individuals.


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


RESULTS
We report that the expression of IFN-λ 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-λR mirrored the expression of serum IFN-λ and was higher in cHCV, compared to controls and HCV-SVR patients, suggesting that elevation of IFN-λ and IFN-λR are HCV-dependent. We further identified that innate immune cell populations expressed complete IFN-λ receptor. In vitro, recombinant IFN-λ 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-λ-DCs failed to induce de novo generation of regulatory T cells. The inhibitory capacity of IFN-λ-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-λ contribute to the understanding of the anti-inflammatory and/or anti-viral potential of IFN-λ in cHCV.
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Angela
A
Dolganiuc
Karen
K
Kodys
Christopher
C
Marshall
Banishree
B
Saha
Shuye
S
Zhang
Shashi
S
Bala
Gyongyi
G
Szabo
D000328:Adult; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology; D008099:Liver / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D017471:Receptors, Interferon / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D000095022:Interferon Lambda
D007372:Interferons; D007378:Interleukins; D017471:Receptors, Interferon; C000624353:interferon-lambda, human; D000095022:Interferon Lambda