title: Breaking tolerance in hepatitis B surface antigen (HBsAg) transgenic mice by vaccination with cross-reactive, natural HBsAg variants.
abstract: Processing exogenous hepatitis B surface antigen (HBsAg) of the hepatitis B virus (HBV) generates the K(b)-binding S(208-215) epitope 1; processing endogenous HBsAg generates the K(b)-binding S(190-197) epitope 2. Cross-reactive CD8(+) T cell responses were primed to epitope 1 but not epitope 2 when mice were immunized with natural HBsAg(ayw), or HBsAg(adw2) variants differing within both epitopes by one or two residues. Expression of HBsAg(ayw) from a transgene in the liver renders (HBs-tg) mice tolerant to epitope 1 of HBsAg(ayw). CD8(+) T cells specific for epitope 1 could be primed in HBs-tg mice by HBsAg(adw2); these specific CD8(+) T cells cross-reacted with epitope 1 processed from the transgene-encoded HBsAg(ayw). The liver of vaccinated HBsAg(ayw) transgenic mice showed severe histopathology and contained functional (IFNgamma-producing), cross-reactive CD8(+) T cells, and vaccinated HBs-tg mice showed reduced antigenemia. Hence, vaccination with natural HBsAg variants from different HBV sero/genotypes can prime cross-reactive, specific CD8(+) T cell immunity that breaks tolerance to HBsAg.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Ulm, Ulm, Germany. reinhold.scirmbeck@medizin.uni-ulm.de
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schirmbeck
authors.forename: Nektarios
authors.initials: N
authors.lastname: Dikopoulos
authors.forename: Marcin
authors.initials: M
authors.lastname: Kwissa
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.forename: Kasper
authors.initials: K
authors.lastname: Lamberth
authors.forename: Soren
authors.initials: S
authors.lastname: Buus
authors.forename: Karl
authors.initials: K
authors.lastname: Melber
authors.forename: Jörg
authors.initials: J
authors.lastname: Reimann
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions; D000939:Epitopes; D006510:Hepatitis B Antibodies / Q000097:blood; D006514:Hepatitis B Surface Antigens / Q000737:chemistry / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000628:therapy*; D007108:Immune Tolerance; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D013154:Spleen / Q000276:immunology; D014611:Vaccination
chemical_list: D000939:Epitopes; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens