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