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Distinct, Cross-Reactive Epitope Specificities of CD8 T Cell Responses Are Induced by Natural Hepatitis B Surface Antigen Variants of Different Hepatitis B Virus Genotypes¹

Petra Riedl^*, Antonio Bertoletti, Ross Lopes, Francois Lemonnier, Jörg Reimann^* and Reinhold Schirmbeck^2,*

^* Department of Internal Medicine I, University of Ulm, Ulm, Germany; Institute of Hepatology and Division of Infection and Immunity, University College London, London, United Kingdom; and Institut National de la Recherche et de la Médicale Unité 580, Institut Necker, Paris, France

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.

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