Peptide-MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity.
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, for example, affinity. We have recently established a high-throughput assay for pMHC-I 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., J. Immunol. 2007. 178: 7890-7901]. Using an affinity-balanced approach, we demonstrated that immunogenic peptides tend to be more stably bound to MHC-I molecules compared with nonimmunogenic peptides. We also developed a bioinformatics method to predict pMHC-I stability, which suggested that 30% of the nonimmunogenic binders hitherto classified as "holes in the T-cell repertoire" can be explained as being unstably bound to MHC-I. Finally, we suggest that nonoptimal anchor residues in position 2 of the peptide are particularly prone to cause unstable interactions with MHC-I. We conclude 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.
Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, Denmark. mikha@sund.ku.dk
Mikkel
M
Harndahl
Michael
M
Rasmussen
Gustav
G
Roder
Ida
I
Dalgaard Pedersen
Mikael
M
Sørensen
Morten
M
Nielsen
Søren
S
Buus
D017951:Antigen Presentation; D019295:Computational Biology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D010455:Peptides / Q000737:chemistry*; D055550:Protein Stability; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D010455:Peptides