Interferon lambda 4 impairs hepatitis C viral antigen presentation and attenuates T cell responses

Qian Chen,Sandro Nuciforo,Maike Hofmann,Robert Thimme,Stefan Wieland,Aleksei Suslov,Volker Lohmann,Nina Hensel,George Rosenberger,Mairene Coto-Llerena,Raphael Dias Teixeira,Markus H Heim,Charlotte K Y Ng,Isabel Fofana

doi:10.1038/s41467-021-25218-x

Abstract

Genetic variants of the interferon lambda (IFNL) gene locus are strongly associated with spontaneous and IFN treatment-induced clearance of hepatitis C virus (HCV) infections. Individuals with the ancestral IFNL4-dG allele are not able to clear HCV in the acute phase and have more than a 90% probability to develop chronic hepatitis C (CHC). Paradoxically, the IFNL4-dG allele encodes a fully functional IFNλ4 protein with antiviral activity against HCV. Here we describe an effect of IFNλ4 on HCV antigen presentation. Only minor amounts of IFNλ4 are secreted, because the protein is largely retained in the endoplasmic reticulum (ER) where it induces ER stress. Stressed cells are significantly weaker activators of HCV specific CD8+ T cells than unstressed cells. This is not due to reduced MHC I surface presentation or extracellular IFNλ4 effects, since T cell responses are restored by exogenous loading of MHC with HCV antigens. Rather, IFNλ4 induced ER stress impairs HCV antigen processing and/or loading onto the MHC I complex. Our results provide a potential explanation for the IFNλ4–HCV paradox.

Highlights

Genetic variants of the interferon lambda (IFNL) gene locus are strongly associated with spontaneous and IFN treatment-induced clearance of hepatitis C virus (HCV) infections
The first description of IFNλ4 in 2013 reported that transfection of cells with an IFNλ4 expression plasmid induced the phosphorylation of the classical IFN signal transducers STAT1 and STAT2 despite the fact that IFNλ4 protein could not be detected in the supernatant of the transfected cells[8]
We found that Sendai virus (SeV) infection-induced changes in the expression levels of 4649 and 3306 genes in the different between IFNλ4 producing (dG) and the TT genotypes, respectively, including a significant enrichment of 2983 genes commonly altered in both genotypes

Summary

Introduction

Genetic variants of the interferon lambda (IFNL) gene locus are strongly associated with spontaneous and IFN treatment-induced clearance of hepatitis C virus (HCV) infections. Stressed cells are significantly weaker activators of HCV specific CD8+ T cells than unstressed cells This is not due to reduced MHC I surface presentation or extracellular IFNλ4 effects, since T cell responses are restored by exogenous loading of MHC with HCV antigens. Compared with the other IFNλ family members, IFNλ4 is very weakly induced by viral infections, poorly expressed, and hardly secreted at all[9,10,11,12,13,14] These properties of IFNλ4 make it difficult to explore functional properties that could explain its negative impact on defense against HCV. Our findings provide mechanistic evidence that IFNλ4 has a negative impact on antigen-dependent immune responses that could explain the “IFNλ4 paradox”

Methods

Results

Conclusion