HBsAg / HLA-A 2 transgenic mice : a model for T cell tolerance to hepatitis B surface antigen in chronic hepatitis B virus infection

Content Provider	Semantic Scholar
Author	Loirat, Delphine Mancini-Bourgine, Maryline Abastado, J.-P. Michel, M.-L.
Abstract	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-g in the periphery, with in vitro cytolytic activity and speci®city for two dominant HBs-speci®c 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-g-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-in ̄ammatory 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-speci®c 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.
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Resource Type	Article