EPITOPE-DEPENDENT SELECTION OF HIGHLY RESTRICTED OR DIVERSE T-CELL RECEPTOR REPERTOIRES IN RESPONSE TO PERSISTENT INFECTION BY EPSTEIN-BARR-VIRUS

The T cell receptor (TCR) repertoires of cytotoxic responses to the im munodominant and subdominant HLA A11-restricted epitopes in the Epstei n-Barr virus (EBV) nuclear antigen-4 were investigated in four healthy virus carriers. The response to the subdominant epitope (EBNA4 399-40 8, designated AVF) was highly restricted with conserved V beta usage a nd identical length and amino acid motifs in the third complementarity -determining regions (CDR3), while a broad repertoire using different combinations of TCR-alpha/beta V and J segments and CDR3 regions was s elected by the immunodominant epitope (EBNA4 416-424, designated IVT). Distinct patterns of interaction with the All-peptide complex were re vealed for each AVF- or IVT-specific TCR clonotype by alanine scanning mutagenesis analysis. Blocking of cytotoxic function by antibodies sp ecific for the CD8 coreceptor indicated that, while AVF-specific TCRs are of high affinity, the oligoclonal response to the IVT epitope incl udes both low- and high-affinity TCRs. Thus, comparison of the memory response to two epitopes derived from the same viral antigen and prese nted through the same MHC class I allele suggests that immunodominance may correlate with the capacity to maintain a broad TCR repertoire.