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

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 develop chronic hepatitis C (CHC) with more than 90% probability. Paradoxically, the IFNL4-dG allele encodes a fully functional IFNÃŽÂ»4 protein with antiviral activity against HCV and coronavirus. Here we describe a hitherto unknown effect of IFNÃŽÂ»4 on HCV antigen presentation. Only minor amounts of IFNÃŽÂ»4 are secreted, because the protein is largely retained in the endoplasmic reticulum (ER) where it induces ER stress. Stressed cells were significantly weaker activators of HCV specific CD8+ T cells. This was not due to reduced MHC I surface presentation or extracellular IFNÃŽÂ»4 effects, since T cell responses could be restored by exogenous loading of MHC with HCV antigens. Rather, IFNÃŽÂ»4 induced ER stress impaired HCV antigen processing and/or loading onto the MHC I complex. Our results provide a potential explanation for the IFNÃŽÂ»4 Ã¢Â€Â“ HCV paradox.

PROVIDER: EGAS00001005396 | EGA |

REPOSITORIES: EGA

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