Modeling the T-helper cell response in acute and chronic hepatitis B virusinfection using T-cell receptor transgenic mice

Chronicity following hepatitis B virus (HBV) infection may be maintained by high levels of viral proteins circulating in the serum. To examine the cha racteristics of T cells capable of co-existing with the secreted hepatitis B e-antigen (HBeAg), T-cell receptor (TCR) transgenic (Tg) mice were produc ed. To insure that HBeAg-specific T cells would not be deleted in the prese nce of serum HBeAg, the TCR alpha and beta -chain genes used to produce the TCR-Tg mice were derived from T-cell hybridomas from HBeAg-Tg mice. A TCR- Tg lineage (11/4-12) was produced that possessed a high frequency (similar to 67%) of CD4(+) T cells that expressed a TCR-Tg specific for the HBeAg. A s predicted, when 11/4-12 TCR-Tg mice were bred with HBeAg-Tg mice no delet ion of the HBeAg-specific CD4(+) T cells occurred in the thymus or the sple en. Functional analysis of the TCR-Tg T cells revealed that the HBeAg-speci fic CD4(+) T cells escaped deletion in the thymus and periphery by virtue o f low avidity. Regardless of their low avidity, HBeAg-specific TCR-Tg T cel ls could be activated by exogenous HBeAg as measured by cytokine production in vitro and T-helper cell function for anti-HBe antibody production in vi tro and in vivo. Furthermore, activated TCR-Tg HBeAg-specific T cells polar ized to the Th, subset were able to elicit liver injury when transferred in to HBeAg or HBcAg-Tg recipients. Therefore, HBeAg-specific CD4(+) T cells t hat can survive deletion or anergy in the presence of circulating HBeAg non etheless are capable of being activated and of mediating liver injury in vi vo. (C) 2001 Elsevier Science B.V. All rights reserved.