International Immunology, Vol. 15, No. 10, pp. 1125-1136,
October 2003
© 2003 Japanese Society for Immunology
HBsAg/HLA-A2 transgenic mice: a model for T cell tolerance to hepatitis B surface antigen in chronic hepatitis B virus infection
1 Unité de Recombinaison et Expression Génétique/INSERM U163 and Unité de Carcinogenèse Hépatique et Virologie Moléculaire/INSERM U370, Institut Pasteur, 28 rue du Dr Roux, 75 015 Paris, France 2 IDM (Immuno-Design Molecules), 172 rue de Charonne, 75011 Paris, France
Correspondence to: M.-L. Michel, Unité Institut Pasteur/INSERM U370, Carcinogenèse Hépatique et Virologie Moléculaire, Batiment Lwoff, Institut Pasteur, 28 rue du Dr Roux, 75015 Paris, France. E-mail: maloum{at}pasteur.fr
Transmitting editor: G. J. Hämmerling
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-
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 Th1 nor Th2 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--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 Th1 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.
Keywords: inflammation, T lymphocyte, vaccination, viral infection
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