Nondeletional T-cell receptor transgenic mice: Model for the CD4(+) T-cellrepertoire in chronic hepatitis B virus infection

Chronicity after infection with the hepatitis B virus (HBV) can occur for a variety of reasons. However, once established, chronicity may be maintaine d by high levels of viral proteins circulating in the serum. To examine the characteristics of T cells capable of coexisting with the secreted hepatit is B e antigen (HBeAg), T-cell receptor (TCR) transgenic (Tg) mice were pro duced. To ensure that HBeAg-specific T cells would not be deleted in the pr esence of serum HBeAg, the TCR alpha- and beta-chain genes used to produce the TCR-Tg mice were derived from T-cell hybridomas produced from immunizin g HBeAg-Tg mice. A TCR-Tg lineage (11/4-12) was produced that possessed a h igh frequency (similar to 67%) of CD4(+) T cells that expressed a Tg TCR sp ecific for the HBeAg. As predicted, when 11/4-12 TCR-Tg mice were bred with HBeAg-Tg mice no deletion of the HBeAg-specific CD4(+) T cells occurred in the thymus or the spleen. Functional analysis of the TCR-Tg T cells reveal ed that the HBeAg-specific CD4(+) T cells escaped deletion in the thymus an d periphery by virtue of low avidity. Regardless of their low avidity, HBeA g-specific TCR-Tg T cells could be activated by exogenous HBeAg, as measure d by cytokine production in vitro and T-helper-cell function for anti-HBe a ntibody production in vitro and in vivo. Furthermore, activated TCR-Tg HBeA g-specific T cells polarized to the Thl subset were able to elicit liver in jury when transferred into HBeAg or HBcAg-Tg recipients. Therefore, HBeAg-s pecific CD4(+) T cells that can survive deletion or anergy in the presence of circulating HBeAg nonetheless are capable of being activated and of medi ating liver injury in vive. The 11/4-12 TCR-TO lineage may serve as a monoc lonal model for the HBe/HBcAg-specific CD4(+) T-cell repertoire present in chronically infected HBV patients.