Hepatitis B virus (HBV) core antigen-specific regulatory T cells confer sustained remission to anti-HBV therapy in chronic hepatitis B with acute exacerbation

• Published in: Human immunology 2011-09, Vol.72 (9), p.687-698
• Main Authors: Koay, Lok-Beng, Feng, I-Che, Sheu, Ming-Jen, Kuo, Hsing-Tao, Lin, Chin-Yih, Chen, Jyh-Jou, Wang, Shih-Ling, Tang, Ling-Yu, Tsai, Sun-Lung
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Antiviral Agents - therapeutic use; Autoimmune diseases; Cell Proliferation; Chronic hepatitis B; Chronic infection; Core protein; Cytotoxicity; Cytotoxicity, Immunologic; Epitope Mapping; Epitopes; Epitopes - metabolism; Forkhead protein; Forkhead Transcription Factors - biosynthesis; Gene profiling; Hepatitis B; Hepatitis B Core Antigens - immunology; Hepatitis B Core Antigens - metabolism; Hepatitis B virus; Hepatitis B virus - immunology; Hepatitis B virus - pathogenicity; Hepatitis B, Chronic - drug therapy; Hepatitis B, Chronic - immunology; Hepatitis B, Chronic - physiopathology; Histocompatibility antigen HLA; Histocompatibility Antigens Class II - metabolism; HLA-class II tetramer; Humans; Immunological tolerance; Immunoregulation; Immunosuppression; Liver; Liver Failure; Lymphocytes T; Mortality; Peripheral blood mononuclear cells; Protein Binding; Regulatory T-cell clone; Remission; Remission Induction; SYFPEITHI score; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; T-Lymphocyte Subsets - virology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; T-Lymphocytes, Regulatory - virology
• ISSN: 0198-8859; 1879-1166
• DOI: 10.1016/j.humimm.2010.11.001

Abstract Acute exacerbations (AEs) of chronic hepatitis B (CH-B) are thought to be the result of breakdown of immune tolerance on the natural history of chronic hepatitis B virus (HBV) infection. Immune tolerance to HBV maintained in CH-B patients without hepatitis is under the control of the host's forkhead box p3-expressing regulatory T cells (Tregs). Its breakdown mimics the occurrence of autoimmune diseases. Severe AEs may lead to liver decompensation and mortalities. Consequently, AEs are currently the major therapeutic targets in patient treatment. In this study, we employed the SYFPEITHI scoring system to identify epitopes on HBV core antigen (HBcAg) for the construction of human leukocyte antigen class II tetramers to measure HBcAg-specific Treg frequencies (Tregf). Upregulation of Treg gene profiling accompanied by increased HBcAg-specific Tregf was detected in AE patients with sustained remission (SR) to anti-HBV therapy. Depletion of Tregs from peripheral blood mononuclear cells enhanced proliferation to HBcAg. HBcAg-specific Treg clones inhibited the killing capacity of cytotoxic T lymphocyte clones in an antigen-independent manner. A greater posttherapy increase in HBcAg-specific Tregf correlated with a higher SR rate to anti-HBV therapy. These results suggest that HBcAg-specific Tregs function as suppressor effectors and confer SR to anti-HBV therapy.