Analyzing the effect of peptide-HLA-binding ability on the immunogenicity of potential CD8+ and CD4+ T cell epitopes in a large dataset

Immunogenicity is a key factor that influences whether a peptide presented by major histocompatibility complex (MHC) can be a T cell epitope. However, peptide immunization experiments have shown that approximately half of MHC class I-binding peptides cannot elicit a T cell response, indicating the importance of analyzing the variables affecting the immunogenicity of MHC-binding peptides. In this study, we hierarchically investigated the contribution of the binding stability and affinity of peptide–MHC complexes to immunogenicity based on the available quantitative data. We found that the immunogenicity of peptides presented by human leukocyte antigen (HLA) class I molecules was still predictable using the experimental binding affinity, although approximately one-third of the peptides with a binding affinity stronger than 500 nM were non-immunogenic, whereas the immunogenicity of HLA-II-presented peptides was predicted well using the experimental affinity and even the predicted affinity. The positive correlation between the binding affinity and stability was only observed in peptide–HLA-I complexes with a binding affinity stronger than 500 nM, which suggested that the stability alone could not be used for the prediction of immunogenicity. A characterization and comparison of the ‘holes’ in the CD8+ and CD4+ T cell repertoire provided an explanation for the observed differences between the immunogenicity of peptides presented by HLA class I and II molecules. We also provided the optimal affinity threshold for the potential CD4+ and CD8+ T cell epitopes. Our results provide important insights into the cellular immune response and the accurate prediction of T cell epitopes.