AIM: To study the mechanisms of hyporesponsiveness of HBV-specific CD4+ T cells by testing TH1 and TH2commitment and regulatory T cells.METHODS: Nine patients with chronic hepatitis B were enrolled. Peripheral blood mononuclear cells were stimulated with HBcAg or HBsAg to evaluate their potential to commit to TH1 and TH2 differentiation.HBcAg-specific activity of regulatory T cells was evaluated by staining with antibodies to CD4, CD25, CTLA-4 and interleukin-10. The role of regulatory T cells was further assessed by treatment with anti-interleukin-10 antibody and depletion of CD4+CD25+ cells.RESULTS: Level of mRNAs for T-bet, IL-12R 32 and IL-4was significantly lower in the patients than in healthy subjects with HBcAg stimulation. Although populations of CD4+CD25highCTLA-4+ T cells were not different between the patients and healthy subjects, IL-10 secreting cells were found in CD4+ cells and CD4+CD25+ cells in the patients in response to HBcAg, and they were not found in cells which were stimulated with HBsAg. Addition of anti-IL-10 antibody recovered the amount of HBcAgspecific TH 1 antibody compared with control antibody (P ＜ 0.01, 0.34% ± 0.12% vs 0.15% ± 0.04%). Deletion of CD4+CD25+ T cells increased the amount of HBcAgspecific TH1 antibody when compared with lymphocytes reconstituted using regulatory T cells (P ＜ 0.01, 0.03% ± 0.02% vs 0.18% ± 0.05%).CONCLUSION: The results indicate that the mechanism of T cell hyporesponsiveness to HBcAg includes activation of HBcAg-induced regulatory T cells in contrast to an increase in TH2-committed cells in response to HBsAg.