Peptide-MHC class I stability is a stronger predictor of CTL immunogenicity than peptide affinity

Peptide-MHC class I stability is a stronger predictor of CTL immunogenicity than peptide affinity Mikkel Harndahla, Michael Rasmussena, Morten Nielsenb, Soren Buusa,∗ a Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, Denmark b Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Denmark Efficient presentation of peptide-MHC class I (pMHC-I) complexes to immune T cells should benefit from a stable peptide- MHC-I interaction.

However, it has been difficult to distinguish stability from other requirements for MHC-I binding e.g. affinity. We have recently established a high-throughput assay for pMHCI stability. Here, we have generated a large database containing stability measurements of pMHC-I complexes, and re-examined a previously reported unbiased analysis of the relative contributions of antigen processing and presentation in defining cytotoxic T lymphocyte (CTL) immunogenicity Assarsson et al., 2007.

Using an affinity-balanced approach, we demonstrated that immunogenic peptides tend to be more stably bound to MHC-I molecules compared with non-immunogenic peptides. We also developed a bioinformatics method to predict pMHC-I stability, which suggested that 30% of the non-immunogenic binders hitherto classified as “holes in the T cell repertoire” can be explained as being unstably bound to MHC-I.

Finally, we suggest that non-optimal anchor residues in position 2 of the peptide are particularly prone to cause unstable interactions with MHC-I.Weconclude that the availability of accurate predictors of pMHC-I stability might be helpful in the elucidation of MHC-I restricted antigen presentation, and might be instrumental in future search strategies for MHC-I epitopes.

Reference Assarsson, E., et al., 2007. J. Immunol. 178, 7890–7901. doi:10.1016/j.molimm.2012.02.025