Towards prediction of degenerate CTL epitope recognition

The cellular immune system is characterized by flexibility with respect to epitope recognition at the level of peptide binding to HLA molecules and HLA-peptide complexes to T-cell receptors (TCRs). For epitopes recognized by cytotoxic T-lymphocytes (CTLs), amino acid substitutions at different positions have varying impact on recognition. By analyzing the frequencies of specific amino acid substitutions at each position in conjunction with HLA-peptide binding and immune-response data, we have developed new methods to predict cross-reactive recognition of epitope variants by CTLs. We derived position-specific substitution matrices (EPSSMs) through the analysis of known HLA ligands and achieved relatively accurate prediction of detrimental and tolerated amino acid substitutions. Initial analysis of amino acid substitutions in CTL epitopes with degenerate recognition showed strong position-specific preferences. This first systematic analysis further suggested that spatial constraint may be the major molecular factor determining the degenerate epitope recognition. As the data cumulates, we anticipate that eventually EPSSMs will be available for prediction of degenerate T-cell epitope recognition.