TY - JOUR
T1 - Peptide-MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity
AU - Harndahl, Mikkel
AU - Rasmussen, Michael
AU - Roder, Gustav
AU - Dalgaard Pedersen, Ida
AU - Sørensen, Mikael
AU - Nielsen, Morten
AU - Buus, Søren
N1 - © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Antigen Presentation
KW - Computational Biology
KW - Histocompatibility Antigens Class I
KW - Humans
KW - Peptides
KW - Protein Stability
KW - T-Lymphocytes, Cytotoxic
U2 - 10.1002/eji.201141774
DO - 10.1002/eji.201141774
M3 - Journal article
C2 - 22678897
SN - 1426-3912
VL - 42
SP - 1405
EP - 1416
JO - Central-European Journal of Immunology
JF - Central-European Journal of Immunology
IS - 6
ER -