title: HBcAg-specific CD4+CD25+ regulatory T cells modulate immune tolerance and acute exacerbation on the natural history of chronic hepatitis B virus infection.
abstract: Acute exacerbations (AEs) of chronic hepatitis B (CH-B) are accompanied by increased T cell responses to hepatitis B core and e antigens (HBcAg/HBeAg). Why patients are immunotolerant (IT) to the virus and why AEs occur spontaneously on the immunoactive phase remain unclear. The role of HBcAg-specific CD4(+)CD25(+) regulatory T (T(reg)) cells in AE and IT phases was investigated in this study. The SYFPEITHI scoring system was employed to predict MHC class II-restricted epitope peptides on HBcAg overlapping with HBeAg that were used for T(reg)-cell cloning and for the construction of MHC class II tetramers to measure T(reg) cell frequencies (T(reg) f). The results showed that HBcAg-specific T(reg) f declined during AE accompanied by increased HBcAg peptide-specific cytotoxic T lymphocyte frequencies. Predominant Foxp3-expressing T(reg) cell clones were generated from patients on the immune tolerance phase, while the majority of Th1 clones were obtained from patients on the immunoactive phase. T(reg) cells from liver and peripheral blood of CH-B patients express CD152 and PD1 antigens that exhibit suppression on PBMCs proliferation to HBcAg. These data suggest that HBcAg peptide-specific T(reg) cells modulate the IT phase, and that their decline may account for the spontaneous AEs on the natural history of chronic hepatitis B virus infection.
authors.affiliation: Hepatogastroenterology Section, Department of Internal Medicine, Chi Mei Medical Center, Yung-Kang City, Tainan, Taiwan.
authors.forename: I-Che
authors.initials: IC
authors.lastname: Feng
authors.forename: Lok-Beng
authors.initials: LB
authors.lastname: Koay
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Sheu
authors.forename: Hsing-Tao
authors.initials: HT
authors.lastname: Kuo
authors.forename: Chi-Shu
authors.initials: CS
authors.lastname: Sun
authors.forename: Chuan
authors.initials: C
authors.lastname: Lee
authors.forename: Wong-Lung
authors.initials: WL
authors.lastname: Chuang
authors.forename: Shuen-Kuei
authors.initials: SK
authors.lastname: Liao
authors.forename: Shih-Ling
authors.initials: SL
authors.lastname: Wang
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Tang
authors.forename: Chia-Ju
authors.initials: CJ
authors.lastname: Cheng
authors.forename: Sun-Lung
authors.initials: SL
authors.lastname: Tsai
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D005260:Female; D006512:Hepatitis B Core Antigens / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens; D000949:Histocompatibility Antigens Class II; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor