Yuan Zhenghong's team from Fudan University reveals a new mechanism by which hepatitis B virus induces immune tolerance by regulating CD8+ T cell thymus development

Hepatitis B virus (HBV) infection can develop into acute or chronic hepatitis B.
Acute hepatitis B is self-limiting and can recover within a few months; while chronic hepatitis B patients carry the virus almost for life, and will continue to progress to liver cirrhosis and liver cancer, etc.
End-stage liver disease is a serious threat to life safety
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A large number of studies have shown that there are a large number of activated CD8+ T cells targeting hepatitis B surface antigen (HBsAg) in adult patients with acute HBV infection, while it is difficult to detect HBsAg-specific CD8+ T cells in patients with chronic infection.
However, its detailed cellular and molecular mechanisms are still unclear
.

Recently, Yuan Zhenghong's team from the Department of Pathogenic Biology and the Key Laboratory of Medical Molecular Virology, Ministry of Education/Health and Health Commission, Fudan University School of Basic Medicine, published an online publication in the Journal of Experimental Medicine entitled: Monocytic MDSCs homing to thymus contribute to age-related Research paper on CD8+ T cell tolerance of HBV
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This study found through clinical cohorts, in vitro experiments and mouse models that hepatitis B virus (HBV) can use monocytic myeloid-derived suppressor cells (mMDSCs) to knock out immature HBV-specific HBV in the thymus CD8+T cells thus established immune tolerance against viruses, and the molecular mechanism was elucidated
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Given that chronic HBV infection mainly comes from infection during infancy and young children, Yuan Zhenghong's team speculates that HBV infection may affect the development of HBV-specific CD8+ T cells in the thymus
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They first cooperated with clinical experts to collect peripheral blood samples from chronic hepatitis B patients aged 2 months to 62 years, and found that the number of HBsAg-specific CD8+ T cells in peripheral blood lymphocytes of infants and young children was negatively correlated with the increase in mMDSCs, while in adult patients The absence of these phenomena suggests that mMDSCs negatively regulate the number of HBsAg-specific CD8+ T cells in an age-dependent manner
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In-depth study found that HBsAg can upregulate the chemokine receptor molecule CCR9 expressed on the surface of mMDSCs by activating ERK1/2 and IL-6 signaling, and mMDSCs can migrate through the interaction of this receptor molecule with its specific ligand CCL25
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In addition, the study also found that mMDSCs can use the mannose receptor (MR) to endocytose HBsAg, and present the HBsAg epitope peptide to the cell surface through the MHC-I pathway, and then interact with immature HBsAg in the thymus.
Specific CD8+CD4-cell interactions, thereby causing the latter to die in a NOX1-dependent manner
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Furthermore, in the tail vein adoptive and mouse parabiosis experiments, it was found that mMDSCs could migrate to the medulla region of the mouse thymus; mMDSCs derived from antibody blocking CCR9 or using CCR9 knockout mice lost the ability to migrate to the thymus
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Then, the researchers established a mouse immune reconstitution model using HBsAg-TCR transgenic mouse bone marrow hematopoietic stem cells, and adopted mMDSCs in this model
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The results showed that the adoption of mMDSCs resulted in a significant decrease in the number of antigen-specific CD8+CD4- cells in the thymus
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Finally, in the HBV hypertensive tail vein mouse replication model, it was confirmed that adoptive mMDSCs can reduce the level of HBsAg-specific CD8+ T cells to help maintain the virus; while blocking CCR9 on the surface of mMDSCs with antibodies is beneficial to restore virus-specific CD8+ T cells and promote HBV clearance
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HBV uses mMDSCs to regulate thymus development of HBsAg-specific CD8+ T cells.
Given that T cells in the periphery are generated from bone marrow and migrate to the thymus to mature, the thymus is the place where T cell antigen tolerance is established.
Cells in the thymus can be negatively screened and age-related.
This study found that HBV can eliminate immature HBsAg-specific T cells in the thymus through mMDSCs, thereby forming a hepatitis B-specific T cell tolerance environment
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This work not only explains the differential mechanism of HBV infection outcomes in patients of different ages, but also provides a scientific basis for the selection of chronic hepatitis B treatment age, suggesting that targeting mMDSCs or their migration may become a novel strategy for the treatment of chronic hepatitis
B.

The research was carried out by Yuan Zhenghong's research group from the Ministry of Education/Key Laboratory of Health and Health Commission of Shanghai Medical College of Fudan University, and the Chronic Hepatitis B Research Group, Hepatitis Department, Laboratory Department and Fudan University Affiliated Public Health Clinical Center Scientific Research Department.
The Department of Infectious Diseases, Pediatric Hospital Affiliated to the University and Duke-National University of Singapore jointly completed the project, and was funded by the Ministry of Science and Technology's "Etiology and Epidemic Prevention Technology System Research" key project, the National Natural Science Foundation of China, and the Chinese Academy of Medical Sciences.
Hepatitis B virus chronic infection cure research innovation unit, etc.

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Researcher Yuan Zhenghong is the corresponding author of the paper, and Dr.
Fang Zhong from the Liver Cancer Research Institute of Zhongshan Hospital Affiliated to Fudan University is the first and co-corresponding author of the paper
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Paper link: https://doi.
org/10.
1084/jem.
20211838 Open for reprinting, welcome to forward to Moments and WeChat groups