Modeling the T-helper cell response in acute and chronic hepatitis B virus infection 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 characteristics of T cells capable of co-existing with the secreted hepatitis B e-antigen (HBeAg), T-cell receptor (TCR) transgenic (Tg) mice were produced. To insure 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 from HBeAg-Tg mice. A TCR-Tg lineage (11/4-12) was produced that possessed a high frequency (approximately 67%) of CD4(+) T cells that expressed a TCR-Tg 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 Th(1) 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.
Chen
M
M
Microbiology and Tumor Biology Center, Karolinska Institute, Huddinge University Hospital, Hälsovägen, Flemingsberg, Sweden.
Sällberg
M
M
Thung
S N
SN
Hughes
J
J
Jones
J
J
Milich
D R
DR
D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019070:Cell Lineage; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D019672:Genes, T-Cell Receptor; D006510:Hepatitis B Antibodies / Q000097:blood; D006513:Hepatitis B e Antigens / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology; D006825:Hybridomas; D008099:Liver / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D019076:Transgenes
D001323:Autoantibodies; D016207:Cytokines; D006510:Hepatitis B Antibodies; D006513:Hepatitis B e Antigens; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta