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

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Genetic variants in the interferon lambda (IFNL) gene locus significantly influence hepatitis C virus (HCV) clearance.
• The IFNL4-dG allele is associated with a high probability of developing chronic hepatitis C (CHC) despite encoding a functional antiviral protein.

Purpose of the Study:

• To investigate the mechanism behind the paradox of the IFNL4-dG allele, which confers susceptibility to chronic hepatitis C despite encoding an antiviral protein.
• To elucidate the effect of the IFNλ4 protein on HCV antigen presentation and T cell responses.

Main Methods:

• Analysis of IFNλ4 protein localization and its effect on endoplasmic reticulum (ER) stress.
• Assessment of HCV-specific CD8+ T cell activation in the presence of IFNλ4-induced ER stress.
• Evaluation of MHC class I (MHC I) surface presentation and exogenous antigen loading assays.

Main Results:

• IFNλ4 protein is primarily retained in the ER, inducing significant ER stress.
• Cells experiencing ER stress exhibit markedly reduced activation of HCV-specific CD8+ T cells.
• Impaired T cell responses are linked to defective HCV antigen processing and/or loading onto MHC I, not reduced MHC I surface expression or extracellular IFNλ4 activity.

Conclusions:

• IFNλ4-induced ER stress disrupts the cellular machinery for antigen processing and presentation, impairing T cell-mediated viral clearance.
• This mechanism provides a molecular explanation for the association between the IFNL4-dG allele and the development of chronic hepatitis C.