期刊
INTERNATIONAL IMMUNOLOGY
卷 15, 期 10, 页码 1125-1136出版社
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxg117
关键词
inflammation; T lymphocyte; vaccination; viral infection
类别
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.
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