Breaking tolerance in hepatitis B surface antigen (HBsAg) transgenic mice by vaccination with cross-reactive, natural HBsAg variants.
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.
Schirmbeck
Reinhold
R
Department of Medical Microbiology and Immunology, University of Ulm, Ulm, Germany. reinhold.scirmbeck@medizin.uni-ulm.de
Dikopoulos
Nektarios
N
Kwissa
Marcin
M
Leithäuser
Frank
F
Lamberth
Kasper
K
Buus
Soren
S
Melber
Karl
K
Reimann
Jörg
J
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
D000939:Epitopes; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens