Influence of T-helper cell subsets and crossregulation in hepatitis B virus infection

Serological and biochemical studies indicate that acute HBV infection is resolved in the context of an efficient cell-mediated immune (CMI) response, whereas, chronic infection is characterized by weak to undetectable CMI responses and relatively efficient humoral immunity. Because humoral immunity and CMI are regulated by different TH subsets, factors which influence the induction of TH1 vs TH2 cells specific for the HBV nucleocapsid antigens (HBcAg, HBeAg) were examined in a murine model system. The factors which affected the HBc/HBeAg-specific TH1/TH2-cell balance included: (1) the structure of the antigen (i.e. HBcAg vs HBeAg); (2) the host MHC and T-cell site recognized; (3) crossregulation between TH1 and TH2 cells; (4) T-cell tolerance, which is more complete in TH1 than in TH2 cells; (5) secreted HBeAg, which preferentially depletes TH1 cells; (6) the HBV-specific subset response could be skewed towards either TH1 or TH2 predominance by cytokine treatment in vivo. The results suggest that the balance between TH1 and TH2 cells specific for the HBc/HBeAgs may be relevant in acute and chronic HBV infections. Importantly, HBeAg-specific TH2 cells preferentially evade tolerance induction as compared to their TH1-cell counterparts. Because HBeAg may act as a tolerogen during the vertical transmission of chronic HBV infection and preferentially depletes TH1 cells in the circulation, the predominance of HBeAg-specific TH2 cells may influence the initiation or maintenance of the chronic carrier state. In this case, cytokine therapy designed to shift a TH2-like response toward TH1 predominance (i.e. IL-12) may be beneficial in the treatment of chronic HBV infection.