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Journal of Virology, August 2000, p. 7587-7599, Vol. 74, No. 16
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Nondeletional T-Cell Receptor Transgenic Mice: Model for the CD4+ T-Cell Repertoire in Chronic Hepatitis B Virus Infection

M. Chen,1 M. Sällberg,2 S. N. Thung,3 J. Hughes,4 J. Jones,4 and D. R. Milich4,*

Microbiology and Tumor Biology Center1 and Department of Immunology, Microbiology, Pathology and Infectious Diseases,2 Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden; Department of Pathology, Mount Sinai Hospital Medical School, New York, New York3; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California4

Received 7 December 1999/Accepted 4 May 2000

Chronicity after infection with the hepatitis B virus (HBV) can occur for a variety of reasons. However, once established, chronicity may be maintained by high levels of viral proteins circulating in the serum. To examine the characteristics of T cells capable of coexisting with the secreted hepatitis B e antigen (HBeAg), T-cell receptor (TCR) transgenic (Tg) mice were produced. To ensure that HBeAg-specific T cells would not be deleted in the presence 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 immunizing HBeAg-Tg mice. A TCR-Tg lineage (11/4-12) was produced that possessed a high frequency (~67%) of CD4+ T cells that expressed a Tg TCR specific 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 revealed that the HBeAg-specific CD4+ T cells escaped deletion in the thymus and periphery by virtue of low avidity. Regardless of their low avidity, HBeAg-specific TCR-Tg T cells could be activated by exogenous HBeAg, as measured by cytokine production in vitro and T-helper-cell function for anti-HBe antibody production in vitro and in vivo. Furthermore, activated TCR-Tg HBeAg-specific T cells polarized to the Th1 subset were able to elicit liver injury when transferred into HBeAg or HBcAg-Tg recipients. Therefore, HBeAg-specific CD4+ T cells that can survive deletion or anergy in the presence of circulating HBeAg nonetheless are capable of being activated and of mediating liver injury in vivo. The 11/4-12 TCR-Tg lineage may serve as a monoclonal model for the HBe/HBcAg-specific CD4+ T-cell repertoire present in chronically infected HBV patients.

* Corresponding author. Mailing address: Vaccine Research Institute of San Diego, 3030 Science Park Rd., San Diego, CA 92121. Phone: (858) 587-9505, ext. 223. Fax: (858) 587-9208. E-mail: dmilich{at}vrisd.org.

Journal of Virology, August 2000, p. 7587-7599, Vol. 74, No. 16
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Chen, M., Sallberg, M., Hughes, J., Jones, J., Guidotti, L. G., Chisari, F. V., Billaud, J.-N., Milich, D. R. (2005). Immune Tolerance Split between Hepatitis B Virus Precore and Core Proteins. J. Virol. 79: 3016-3027 [Abstract] [Full Text]  
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