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

Mikkel Nors Harndahl, Michael Rasmussen, Morten Nielsen, Soren Buus

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    Abstract

    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
    Original languageEnglish
    Title of host publicationMolecular Immunology
    Volume51
    PublisherElsevier
    Publication date2012
    Pages11
    DOIs
    Publication statusPublished - 2012
    Event7th International EMBO Workshop on Antigen Presentation and Processing - Amsterdam, Netherlands
    Duration: 24 Apr 201227 May 2012

    Conference

    Conference7th International EMBO Workshop on Antigen Presentation and Processing
    CountryNetherlands
    CityAmsterdam
    Period24/04/201227/05/2012

    Cite this

    Harndahl, M. N., Rasmussen, M., Nielsen, M., & Buus, S. (2012). Peptide-MHC class I stability is a stronger predictor of CTL immunogenicity than peptide affinity. In Molecular Immunology (Vol. 51, pp. 11). Elsevier. https://doi.org/10.1016/j.molimm.2012.02.025