IFNL3 mediates interaction between innate immune cells: Implications for hepatitis C virus pathogenesis

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Common Interferon lambda 3 (IFNL3) variants influence Hepatitis C Virus (HCV) infection clearance.
• The precise functional mechanisms of these IFNL3 genetic variants remain unclear.
• Limited data exists on IFNL3's role within innate immune cells during HCV infection.

Purpose of the Study:

• To investigate IFNL3 and its receptor IFNLR1 expression in blood immune cell subsets and HCV-infected liver tissues.
• To assess the responsiveness of these cells to IFNL3.
• To explore the association between IFNL3 polymorphisms (rs8099917, rs12979860) and IFNL3 expression.

Main Methods:

• Genotyping of IFNL3 SNPs (rs8099917 and rs12979860) in study participants.
• Quantification of IFNL3 and IFNLR1 expression in peripheral blood mononuclear cells (PBMCs), monocytes, plasmacytoid dendritic cells (pDCs), and HCV liver biopsies.
• Assessment of cellular response to IFNL3 via MxA up-regulation.

Main Results:

• Unstimulated blood immune cells exhibit significantly higher IFNL3 levels compared to HCV liver biopsies.
• Plasmacytoid dendritic cells (pDCs) are the primary producers of IFNLR1, particularly upon IFN-α stimulation.
• PBMCs, monocytes, and pDCs demonstrate responsiveness to IFNL3, evidenced by MxA up-regulation.
• No significant differences in IFNL3 expression were found across different genotypes of the studied IFNL3 SNPs.

Conclusions:

• Peripheral blood pDCs are identified as the predominant IFNL3 producers, surpassing levels found in HCV-infected livers.
• Innate immune cells, especially pDCs, play a crucial role in mediating the functional impact of IFNL3 genetic variations in HCV patients.
• This study highlights innate immunity as central to understanding IFNL3 polymorphism effects on HCV infection outcomes.