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Stem Cell-Derived Viral Ag-Specific T Lymphocytes Suppress HBV Replication in Mice
Published on: September 25, 2019
Maternal-Derived Hepatitis B Virus e Antigen Alters Macrophage Function in Offspring to Drive Viral Persistence after
Yongjun Tian1, Cheng-Fu Kuo1, Omid Akbari1
1Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Abstract:
In contrast to horizontal transmission of hepatitis B virus (HBV) between adults, which often leads to self-limited acute infection, vertical transmission of HBV from mother to child often leads to chronic infection. However, the mechanisms linking vertical transmission with chronic infection are not known. We developed a mouse model to study the effect of maternal HBV infection on HBV persistence in offspring and found that HBV carried by the mother impaired CD8(+) T cell responses to HBV in her offspring, resulting in HBV persistence. This impairment of CD8(+) T cell responses was mediated by hepatic macrophages, which were predisposed by maternal HBV e antigen (HBeAg) to support HBV persistence by upregulation of inhibitory ligand PD-L1 and altered polarization upon restimulation with HBeAg. Depletion of hepatic macrophages led to CD8(+) T cell activation and HBV clearance in the offspring, raising the possibility of targeting macrophages to treat chronic HBV patients.
Insights
Maternal hepatitis B virus (HBV) infection impairs offspring CD8(+) T cell responses, causing chronic HBV. Hepatic macrophages mediate this via PD-L1, suggesting macrophage-targeted therapies for chronic HBV.
Area of Science:
- Immunology
- Virology
- Hepatology
Background:
- Vertical transmission of Hepatitis B virus (HBV) from mother to child frequently results in chronic infection, unlike adult horizontal transmission.
- The underlying mechanisms connecting vertical HBV transmission to chronic infection remain largely unknown.
Purpose of the Study:
- To investigate the impact of maternal HBV infection on HBV persistence in offspring using a mouse model.
- To elucidate the immunological mechanisms responsible for HBV persistence following vertical transmission.
Main Methods:
- Development of a mouse model for maternal HBV infection.
- Analysis of CD8(+) T cell responses in HBV-infected offspring.
- Investigation of the role of hepatic macrophages and PD-L1 expression in modulating T cell responses.
- Assessment of the therapeutic potential of hepatic macrophage depletion.
Main Results:
- Maternal HBV infection led to impaired CD8(+) T cell responses in offspring, resulting in HBV persistence.
- Hepatic macrophages, influenced by maternal HBV e antigen (HBeAg), upregulated PD-L1, suppressing T cell responses.
- Depletion of hepatic macrophages restored CD8(+) T cell activation and promoted HBV clearance in offspring.
Conclusions:
- Maternal HBV infection establishes an immunosuppressive hepatic environment in offspring, mediated by macrophages, leading to viral persistence.
- Targeting hepatic macrophages presents a potential therapeutic strategy for treating chronic HBV infection.
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