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The impact of the MHC class I peptide binding stability on the immunogenicity of particular peptide Ags in class I-restricted cytotoxic T lymphocyte responses is not clearly established. Therefore, we have determined the dissociation rate of each peptide from MHC class I at 37 degrees C and compared this to that of a consensus CTL epitope. Newly defined immunogenic peptides formed relatively stable MHC-peptide complexes as shown by their low dissociation rates, whereas nonimmunogenic peptides displayed high dissociation rates. In addition virtually all previously described HLA-A*0201-restricted T cell epitopes showed low dissociation rates. Furthermore, we show that the immunogenicity of HIV-1-derived peptides can be predicted more accurately by their dissociation rate than by the MHC class I binding affinity. Selection of peptides based on affinity and their dissociation rate leads to a more precise identification of candidate CTL epitopes than selection based on affinity alone. These results help to understand why some peptides are recognized by CTL and, along with detailed knowledge of protein processing rules, therefore have important implications for the selection of peptides in peptide-based vaccines.

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MHC‐class‐I‐restricted cytotoxic T lymphocytes (CTL) specific for tumor‐associated antigens expressed by malignant cells are important components of the immune response against cancer. Recently, tumor‐specific CTL could be generated in vitro, with responding lymphocytes from the blood of healthy blood donors. In the present study, we confirm that peptide‐specific stimulation in vitro can induce high‐affinity CTL capable of recognizing tumor cells expressing the appropriate tumor antigen. These tyrosinase‐specific CTL display a restricted usage of TCRAV and TCRBV gene segments but of diverse CDR3 regions, resulting in a distinct fine‐specificity for each CTL clone. This suggests that, similar to in vivo priming, peptide‐pulsed APC are capable of stimulating a T‐cell response in vitro expressing a limited TCR repertoire against autologous tumors. The generated CTL can recognize their target structure with high affinity, and this correlates in part with tumor‐cell lysis. This methodology may be used to treat melanoma patients with infusion of ex vivo‐induced and ‐expanded CTL. Int. J. Cancer 72:1122–1128, 1997. © 1997 Wiley‐Liss, Inc.

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