Distinct, cross-reactive epitope specificities of CD8 T cell responses are induced by natural hepatitis B surface antigen variants of different hepatitis B virus genotypes.
We investigated the specific and cross-reactive CD8 T cell immunity to three natural variants (of different geno/serotype) of the small hepatitis B surface Ag (or S protein). The D(d)-binding variants of the S(201-209) epitope showed different immunogenicity. The loss of the consensus C-terminal (P9) anchor abrogated its immunogenicity. In contrast, a conservative (serine vs asparagine) exchange at P7 primed cross-reactive CD8 T cells that preferentially recognized the priming variant. Cross-reactive CD8 T cell responses to a variant could be primed in mice tolerant to an alternative variant of the D(d)-binding S(201-209) peptide. Loss of the C-terminal (P10) anchor in S(185-194) eliminated its immunogenicity in HLA-A*0201(A2)-transgenic mice but two conservative exchanges (leucine vs valine in P2, and leucine vs isoleucine in P6) in S(208-216) generated cross-reactive CD8 T cell responses with strong preference for the priming variant. Similar cross-reactive recognition of variant envelope epitopes were also found in S(208-216)-specific CD8 T cells from hepatitis B virus (HBV)-infected patients. Distinct CD8 T cell populations cross-reactive to natural variants of class I-restricted HBV epitopes can be primed by vaccination (of mice) or natural infection (of humans), and they may play a role in the "spontaneous remission" or the specific immunotherapy of chronic HBV infection.
Department of Internal Medicine I, University of Ulm, Germany.
Petra
P
Riedl
Antonio
A
Bertoletti
Ross
R
Lopes
Francois
F
Lemonnier
Jörg
J
Reimann
Reinhold
R
Schirmbeck
D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D003429:Cross Reactions / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen; D006509:Hepatitis B / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D006515:Hepatitis B virus / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data
D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D006514:Hepatitis B Surface Antigens