Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 42, Issue 6, Pages 1405-1416Publisher
WILEY
DOI: 10.1002/eji.201141774
Keywords
Dissociation; Immunogenicity; MHC; Peptide; Stability
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Funding
- NIH [HHSN272200900045C]
- Novo Nordisk Fonden [NNF10CC1016517] Funding Source: researchfish
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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: 78907901]. 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.
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