Proline substitution independently enhances H-2Db complex stabilization and TCR recognition of melanoma-associated peptides

Authors

  • Hannes Uchtenhagen,

    1. Science for Life Laboratory, Center for Infectious Medicine (CIM), Department of Medicine, Karolinska Insitutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    Search for more papers by this author
  • Esam T. Abualrous,

    1. Molecular Life Science, Jacobs University Bremen, Bremen, Germany
    Search for more papers by this author
  • Evi Stahl,

    1. Science for Life Laboratory, Center for Infectious Medicine (CIM), Department of Medicine, Karolinska Insitutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    Search for more papers by this author
  • Eva B. Allerbring,

    1. Science for Life Laboratory, Center for Infectious Medicine (CIM), Department of Medicine, Karolinska Insitutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    Search for more papers by this author
  • Marjolein Sluijter,

    1. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
    Search for more papers by this author
  • Martin Zacharias,

    1. Department of Physics, Technical University of Munich, Munich, Germany
    Search for more papers by this author
  • Tatyana Sandalova,

    1. Science for Life Laboratory, Center for Infectious Medicine (CIM), Department of Medicine, Karolinska Insitutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    Search for more papers by this author
  • Thorbald van Hall,

    1. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
    Search for more papers by this author
  • Sebastian Springer,

    1. Molecular Life Science, Jacobs University Bremen, Bremen, Germany
    Search for more papers by this author
  • Per-Åke Nygren,

    1. Division of Protein Technology, AlbaNova University Center, KTH Royal Institute of Technology, Stockholm, Sweden
    Search for more papers by this author
  • Adnane Achour

    Corresponding author
    1. Science for Life Laboratory, Center for Infectious Medicine (CIM), Department of Medicine, Karolinska Insitutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    • Full correspondence Dr. Adnane Achour, Science for Life Laboratory, Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden

      e-mail: adnane.achour@ki.se

      See accompanying commentary:

      http://dx.doi.org/10.1002/eji.201344095

    Search for more papers by this author

  • See accompanying commentary by Hickman and Yewdell

Abstract

The immunogenicity of H-2Db (Db) restricted epitopes can be significantly increased by substituting peptide position 3 to a proline (p3P). The p3P modification enhances MHC stability without altering the conformation of the modified epitope allowing for T-cell cross-reactivity with the native peptide. The present study reveals how specific interactions between p3P and the highly conserved MHC heavy chain residue Y159 increase the stability of Db in complex with an optimized version of the melanoma-associated epitope gp10025–33. Furthermore, the p3P modification directly increased the affinity of the Db/gp10025–33-specific T-cell receptor (TCR) pMel. Surprisingly, the enhanced TCR binding was independent from the observed increased stability of the optimized Db/gp10025–33 complex and from the interactions formed between p3P and Y159, indicating a direct effect of the p3P modification on TCR recognition.

Ancillary