Acute exacerbations of chronic hepatitis B are accompanied by decline of core antigen-specific regulatory T-cell frequencies: Implications for successful anti-HBV treatments

Background and Aims: Acute exacerbations (AEs) of perinatally-acquired chronic hepatitis B (CHB) are accompanied by increased T cell responses to hepatitis B core and e antigens (HBcAg & HBeAg). Naturally-arising forkhead transcription factor Foxp3 (forkhead box p3)-expressing CD4⁺CD25⁺ regulatory T (T_reg) cells are thought to be important in the control of infectious diseases. This study aimed to investigate whether HBcAg-specific T_reg cells play a role in modulating spontaneous AEs and in influencing the outcome of anti-hepatitis B virus (HBV) treatments. Methods: The SYFPEITHI scoring system was employed to predict epitope peptides on HBcAg overlapping with HBeAg for the construction of peptide-HLA class II tetramers to measure HBcAg-specific T_reg cell frequencies (T_reg f). Results: HBcAg-specific T_reg f declined significantly in association with increased HBcAg-specific cytotoxic T lymphocyte frequencies during spontaneous AEs without treatment. Vigorous in vitro expansion of CD4+CD25+ T_reg cells from CHB patients responding to HBcAg and/or its peptides plus interleukin-2 (IL-2) was consistently detected. Depletion of T_reg cells from peripheral blood mononuclear cells enhanced proliferation to HBcAg. In contrast, patients with AEs who received anti-HBV treatments with oral nucleoside analogues or interferon-alpha injection revealed that more posttreatment increase of HBcAg-specific T_reg f correlated with a higher sustained remission rate to the therapy. Conclusions: These data indicate that HBcAg-specific T_reg cells from perinatally-acquired CHB patients are proliferative to HBcAg and its peptides and exhibit suppressor activity. They play a crucial role in modulating spontaneous AEs and in successful anti-HBV treatments.