HBsAg/HLA-A2 transgenic mice: a model for T cell tolerance to hepatitis B surface antigen in chronic hepatitis B virus infection
| Autor: | J.‐P. Abastado, D. Loirat, Marie-Louise Michel, M. Mancini‐Bourgine |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
CD4-Positive T-Lymphocytes
HBsAg T-Lymphocytes T cell Genetic Vectors Molecular Sequence Data Immunology Mice Transgenic CD8-Positive T-Lymphocytes Epitope Mice Hepatitis B Chronic HLA-A2 Antigen MHC class I Immune Tolerance Vaccines DNA medicine Animals Humans Immunology and Allergy Cytotoxic T cell Amino Acid Sequence Antigen-presenting cell Hepatitis B Surface Antigens biology General Medicine Th1 Cells Adoptive Transfer Virology Molecular biology Disease Models Animal medicine.anatomical_structure biology.protein Antibody Whole-Body Irradiation CD8 Plasmids |
| Zdroj: | International Immunology. 15:1125-1136 |
| ISSN: | 1460-2377 |
| DOI: | 10.1093/intimm/dxg117 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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