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Individuals with the ancestral <jats:italic>IFNL4-dG<\/jats:italic> 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 <jats:italic>IFNL4-dG<\/jats:italic> allele encodes a fully functional IFN\u03bb4 protein with antiviral activity against HCV. Here we describe an effect of IFN\u03bb4 on HCV antigen presentation. Only minor amounts of IFN\u03bb4 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<jats:sup>+<\/jats:sup> T cells than unstressed cells. This is not due to reduced MHC I surface presentation or extracellular IFN\u03bb4 effects, since T cell responses are restored by exogenous loading of MHC with HCV antigens. Rather, IFN\u03bb4 induced ER stress impairs HCV antigen processing and\/or loading onto the MHC I complex. Our results provide a potential explanation for the IFN\u03bb4\u2013HCV paradox.<\/jats:p>","DOI":"10.1038\/s41467-021-25218-x","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T10:04:26Z","timestamp":1628762666000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Interferon lambda 4 impairs hepatitis C viral antigen presentation and attenuates T cell responses"],"prefix":"10.1038","volume":"12","author":[{"given":"Qian","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7596-1250","authenticated-orcid":false,"given":"Mairene","family":"Coto-Llerena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksei","family":"Suslov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9642-7508","authenticated-orcid":false,"given":"Raphael Dias","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Fofana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1863-1869","authenticated-orcid":false,"given":"Sandro","family":"Nuciforo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8410-8833","authenticated-orcid":false,"given":"Maike","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1417-4135","authenticated-orcid":false,"given":"Robert","family":"Thimme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6401-6149","authenticated-orcid":false,"given":"Nina","family":"Hensel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8719-7608","authenticated-orcid":false,"given":"Volker","family":"Lohmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6100-0026","authenticated-orcid":false,"given":"Charlotte K. 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