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

Hannes Uchtenhagen, Esam T. Abualrous, Evi Stahl, Eva B. Allerbring, Marjolein Sluijter, Martin Zacharias, Tatyana Sandalova, Thorbald van Hall, Sebastian Springer, Per Åke Nygren, Adnane Achour

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)3051-3060
Number of pages10
JournalEuropean Journal of Immunology
Volume43
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

Keywords

  • MHC
  • Structural Biology
  • T-cell epitope
  • TCR
  • Tumor antigen

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