The hepatitis B precore Ag (HBeAg) is a secreted nonparticulate version of the viral nucleocapsid hepatitis B core Ag (HBcAg), and its function is unknown. A proportion of HBeAg-specific Th cells evade deletion/anergy in HBeAg-transgenic (Tg) mice and mediate anti-HBe "autoantibody" (autoAb) production after in vivo activation with the appropriate Th cell peptide. This model system was used to determine how secretory HBeAg may effect deletion of Th cells in the periphery. For this purpose, HBeAg-Tg mice were bred with Fas and Fas ligand (FasL)-defective lpr/lpr and gld/gld mutant mice. Fas-FasL interactions mediate activation-induced apoptosis in the periphery. In HBeAg-Tg/+ mice, high-titrated anti-HBe autoAb was produced that was exclusively composed of the IgG1 isotype (i.e., Th2-like profile). In contrast, HBeAg-Tg/lpr and HBeAg-Tg/gld mice produced significantly less anti-HBe autoAb, and the IgG isotype patterns were broadened to include IgG2a, IgG2b and IgG3 as well as IgG1 (i.e., mixed Th1/Th2-like profile). These results suggest that HBeAg-specific Th1 cells are preferentially depleted by Fas-FasL-mediated interactions. The effect of circulating HBeAg on HBcAg-specific Th1 cells was also examined by transferring HBe/HBcAg-specific Th cells into dual HBeAg- and HBcAg-expressing Tg recipient mice. The presence of serum HBeAg ablated the expected Th1-mediated anti-HBc Ab response and shifted it toward a Th2 phenotype. These results suggest that in the context of a hepatitis B viral infection, circulating HBeAg has the potential to preferentially deplete inflammatory HBeAg- and HBcAg-specific Th1 cells that are necessary for viral clearance, thereby promoting hepatitis B virus persistence.