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

Qian Chen, Mairene Coto-Llerena, Aleksei Suslov, Raphael Dias Teixeira, Isabel Fofana, Sandro Nuciforo, Maike Hofmann, Robert Thimme, Nina Hensel, Volker Lohmann, Charlotte K. Y. Ng, George Rosenberger, Stefan Wieland and Markus H. Heim ()
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Qian Chen: University of Basel
Mairene Coto-Llerena: University of Basel
Aleksei Suslov: University of Basel
Raphael Dias Teixeira: Biozentrum, University of Basel
Isabel Fofana: University of Basel
Sandro Nuciforo: University of Basel
Maike Hofmann: University Hospital Freiburg
Robert Thimme: University Hospital Freiburg
Nina Hensel: University Hospital Freiburg
Volker Lohmann: University of Heidelberg
Charlotte K. Y. Ng: University of Bern
George Rosenberger: University of Basel
Stefan Wieland: University of Basel
Markus H. Heim: University of Basel

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25218-x

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