POLYCLONALITY AND MULTISPECIFICITY OF THE CTL RESPONSE TO A SINGLE VIRAL EPITOPE

The molecular anatomy of an immunodominant, L-d restricted CTL epitope located between residues 28-39 in hepatitis B surface Ag was defined to explore the immunologic constraints on mutational escape from the C TL response during a viral infection. Using a panel of hepatitis B sur face Ag residue 28-39-specific CTL clones, the response to this epitop e was found to be extremely diverse at the level of TCR fine specifici ty and beta-chain usage. Although each clone recognized shared as well as unique residues within the epitope as TCR contact sites, even the shared residues were recognized differently by different TCRs. Despite these differences, all clones were comparably cytolytic following Ag stimulation and produced similar amounts of antiviral cytokines previo usly shown to inhibit HEV replication. These results demonstrate that the CTL response to individual viral epitopes can he markedly polyclon al and multispecific, such that mutational inactivation of a single TC R contact site will not usually lead to viral escape from all CTL clon es of the same epitope specificity. Given these constraints and the fa ct that the CTL response is usually directed against several different epitopes during most viral infections, mutational inactivation of a s ingle epitope is not likely to be sufficient to cause viral persistenc e.