THE HEPATITIS-B VIRUS CORE AND E-ANTIGEN ELICIT DIFFERENT TH CELL SUBSETS - ANTIGEN STRUCTURE CAN AFFECT TH CELL PHENOTYPE

Secretion of the hepatitis B virus (HBV e antigen (HBeAg) has been con served throughout the evolution of hepadnaviruses. However, the functi on of this secreted form of the viral nucleoprotein remains enigmatic, It has been suggested that HBeAg functions as an immunomodulator. We therefore examined the possibility that the tno structural forms of th e viral nucleoprotein, the particulate HBV core (HBcAg) and the nonpar ticulate HBeAg, may preferentially elicit different T helper (Th) cell subsets. For this purpose, mice were immunized with recombinant HBcAg and HBeAg in the presence and absence of adjuvants, and the immunoglo bulin G (IgG) isotype profiles of anti-HBc and anti-HBe antibodies wer e determined. Second, in vitro cytokine production by HBcAg- and HBeAg -primed Th cells was measured. The immunogenicity of HBcAg, in contras t to that of HBeAg, did not require the use of adjuvants. Furthermore, HBcAg elicited primarily IgG2a and IgG2b anti-HBe antibodies, with a low level of IgG3, and no IgG1 anti-HBc antibodies. In contrast, tile anti-HBe antibody response was dominated by the IgG1 isotype; low leve ls of IgG2a or IgG2b anti-HBe antibodies and no IgG3 anti-HBe antibodi es were produced. Cytokine production by HBcAg- and HBeAg-primed Th ce lls,vas consistent with the IgG isotype profiles. HBcAg-primed Th cell s efficiently produced interleukin-2 (IL-2) and gamma interferon IFN-g amma) and low levels of IL-4. Conversely, efficient IL-4 production an d lesser amounts of IFN-gamma were elicited by HBeAg immunization. The results indicate that HBcAg preferentially, but not exclusively, elic its Th-1-like cells and that HBeAg preferentially, but not exclusively , elicits Th-0 or Th-2-like cells. Because HBcAg and the HBeAg are cro ss-reactive in terms of Th cell recognition, these findings demonstrat e that Th cells with the same specificity can develop into different T h subsets based on the structural form of the immunogen. These results may have relevance to chronic HBV infection, Circulating HBeAg may do wn-regulate antiviral clearance mechanisms by virtue of eliciting anti -inflammatory Th-2-like cytokine production, Last, the influence of an tigen structure on Th cell phenotype was not absolute and could be mod ulated by in vivo cytokine treatment, For example, IFN-alpha treatment inhibited HBeAg-specific Th-2-mediated antibody production and altere d the IgG anti-HBe isotype profile toward the Th-1 phenotype.