Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is mediated by an inappropriate attack by HBV-specific T cells in patients. However, this immunopathogenic process has not been clarified because of the lack of a suitable animal model. Here, we used immunocompetent Fah−/− mice as the recipients in the adoptive transfer of HBsAg+ hepatocytes from HBs-Tg mice to replace the recipient hepatocytes (HBs-HepR). HBs-HepR mice exhibited persistent HBsAg expression with chronic hepatitis and eventually developed HCC with a prevalence of 100%. HBsAg-specific CD8+ T cells were generated and specifically and continuously induced hepatocyte apoptosis with progressive chronic inflammation, and the depletion of CD8+ T cells or their deficiency prevented HCC, which could then be reproduced by the transfer of HBsAg-specific CD8+ T cells. In summary, our results demonstrated that CD8+ T cells plays a critical role in HBsAg-driven inflammtion and HCC tumorigenesis.
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Raw sequencing data have been deposited in GEO Datasets with the GEO accession number GSE130880.
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We thank Dr. Zhexiong Lian for providing the CD8 KO mice and Dr. Xin Wang for providing the Fah KO mice. We thank the NIH tetramer core facility for kindly providing HBsAg-Tetramer used in this study. This work was supported by the Chinese Academy of Science (XDB29030201), the National Key R&D Program of China (2018YFA0507403, 2017ZX10202203-009-002), and the Natural Science Foundation of China (#81788101, 81671554, 91542000, 81821001).
The authors declare no competing interests.
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Hao, X., Chen, Y., Bai, L. et al. HBsAg-specific CD8+ T cells as an indispensable trigger to induce murine hepatocellular carcinoma. Cell Mol Immunol (2019) doi:10.1038/s41423-019-0330-1
- HBsAg-specific CTL