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HBsAg/HLA‐A2 transgenic mice: a model for T cell tolerance to hepatitis B surface antigen in chronic hepatitis B virus infection

HBsAg/HLA‐A2 transgenic mice: a model for T cell tolerance to hepatitis B surface antigen in... 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‐γ 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‐γ‐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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Immunology Oxford University Press

HBsAg/HLA‐A2 transgenic mice: a model for T cell tolerance to hepatitis B surface antigen in chronic hepatitis B virus infection

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References (57)

Publisher
Oxford University Press
Copyright
The Japanese Society for Immunology
ISSN
0953-8178
eISSN
1460-2377
DOI
10.1093/intimm/dxg117
Publisher site
See Article on Publisher Site

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‐γ 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‐γ‐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.

Journal

International Immunology – Oxford University Press

Published: Oct 1, 2003

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