HBsAg/HLA-A2 transgenic mice: a model for T cell tolerance to hepatitis B surface antigen in chronic hepatitis B virus infection.
A humanized murine model was developed to study T cell tolerance to the hepatitis B surface antigen (HBsAg) that is present in sera of hepatitis B virus chronic carriers. The HBsAg/HLA-A2 double-transgenic mice express a chimeric HLA-A2 MHC class I molecule and a high amount of the HBsAg in the liver that is secreted and present in sera during the animal's lifetime. In these mice, injection of plasmid DNA encoding HBsAg induced a high frequency of CD8(+) T cells secreting IFN-gamma in the periphery, with in vitro cytolytic activity and specificity for two dominant HBs-specific HLA-A2-restricted epitopes. Nevertheless, the DNA-based immunization elicited neither T(h)1 nor T(h)2 CD4(+) T cell responses. Despite a high concentration of HBsAg in sera, these mice developed an immunocompetent CD8(+) T cell repertoire towards the viral self-antigen, whereas the CD4(+) T cell repertoire was tolerized. In the absence of a CD4(+) T cell response, the IFN-gamma-secreting CD8(+) T cells primed by DNA-based immunization were unable to exert their antiviral functions in vivo on liver cells expressing the transgene product. However, when pro-inflammatory stimuli were given before or after DNA-based immunization, the HBsAg was cleared from the serum. This effect was antibody dependent and associated with the detection of an HBs-specific T(h)1 CD4(+) T cell response in the periphery. This model provides evidence that HBsAg displayed a strong tolerogenic effect on the CD4(+) T cell compartment that is associated with a defect in CD8(+) T cell effector functions in vivo.
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005822:Genetic Vectors; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010957:Plasmids; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics; D014916:Whole-Body Irradiation
D015789:HLA-A2 Antigen; D006514:Hepatitis B Surface Antigens; D019444:Vaccines, DNA