Feedback regulation of IFN-alpha/beta signaling by Axl receptor tyrosine kinase modulates HBV immunity

Hepatitis B virus (HBV) is known to cause age-dependent infection outcomes wherein most infection during young age results in chronicity. The age-related immune mechanism underlying the differential outcome remains elusive. By using hydrodynamic injection of the replication-competent pAAV-HBV, we established a mouse model in which HBV persistence was generated in 4-5 w/o C57BL/6 young mice, but not in adult mice of over 10 w/o.

The HBV-tolerant young mice expressed higher interferon (IFN)-a/b in the hepatocytes and intrahepatic plasmacytoid DCs (pDCs) than the adult after pAAV-HBV injection. Paradoxically, excessive IFN-a/b expression of the young mice was associated with induction of the Axl regulatory pathway and expansion of intrahepatic Treg cells. In line with these findings, augmented IFN-b expression increased HBV persistence of the adult mice and IFN-a/b signaling blockage decreased HBV persistence of the young mice. Accordingly, Axl overexpression decreased HBV clearance of the adult mice whereas Axl silencing enhanced HBV clearance of the young mice. In vitro, IFN-b priming of bone marrow-derived pDCs enhanced Treg cell differentiation.

These findings suggest that the age-dependent HBV chronicity is attributed to IFN-b-Axl immune regulation, which is selectively induced in the young mice by excessive IFN-a/b production at early stage of HBV infection.