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Pedro-Otavio de Campos-Lima^*, Victor Levitsky^*, Martha P. Imreh^*, Riccardo Gavioli, and Maria G. Masucci^*

From the ^* Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77, Stockholm, Sweden; and Institute of Biochemistry and Molecular Biology, University of Ferrara Medical School, 44100 Ferrara, Italy

The T cell receptor (TCR) repertoires of cytotoxic responses to the immunodominant and subdominant HLA A11–restricted epitopes in the Epstein-Barr virus (EBV) nuclear antigen-4 were investigated in four healthy virus carriers. The response to the subdominant epitope (EBNA4 399-408, designated AVF) was highly restricted with conserved Vβ usage and identical length and amino acid motifs in the third complementarity-determining regions (CDR3), while a broad repertoire using different combinations of TCR-/β V and J segments and CDR3 regions was selected by the immunodominant epitope (EBNA4 416-424, designated IVT). Distinct patterns of interaction with the A11–peptide complex were revealed for each AVF- or IVT-specific TCR clonotype by alanine scanning mutagenesis analysis. Blocking of cytotoxic function by antibodies specific for the CD8 coreceptor indicated that, while AVF-specific TCRs are of high affinity, the oligoclonal response to the IVT epitope includes both low- and high-affinity TCRs. Thus, comparison of the memory response to two epitopes derived from the same viral antigen and presented through the same MHC class I allele suggests that immunodominance may correlate with the capacity to maintain a broad TCR repertoire.

The authors are indebted to Andrew J. McMichael for helpful comments on the manuscript.

This investigation was supported by grants from the Swedish Cancer Society, the Pediatric Cancer Foundation, the Karolinska Institute, and the Magnus Bergwal Stiftelse, Stockholm, Sweden. V. Levitsky and M.P. Imreh are supported by fellowships from the Cancer Research Institute, New York and Concern Foundation, Los Angeles. P.-O. de Campos-Lima was partially supported by a fellowship from the Swedish Royal Academy of Sciences. The research in the laboratory of RG was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC).

The first two authors have contributed equally to this work and are placed in alphabetical order.

¹ Abbreviations used in this paper: EBNA, Epstein-Barr virus nuclear antigen; CDR3, third complementarity determining region; FW, framework; LCL, lymphoblastoid cell lines.

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