Peptide length determines the outcome of TCR/peptide-MHCI engagement

Julia Ekeruche-Makinde, John J Miles, Hugo A van den Berg, Ania Skowera, David K Cole, Garry Dolton, Andrea J A Schauenburg, Mai Ping Tan, Johanne M Pentier, Sian Llewellyn-Lacey, Kim M Miles, Anna M Bulek, Mathew Clement, Tamsin Williams, Andrew Trimby, Mick Bailey, Pierre Rizkallah, Jamie Rossjohn, Mark Peakman, David A PriceScott R Burrows, Andrew K Sewell, Linda Wooldridge

Research output: Contribution to journalArticle (Academic Journal)peer-review

61 Citations (Scopus)

Abstract

αβ-TCRs expressed at the CD8(+) T-cell surface interact with short peptide fragments (p) bound to MHC class I molecules (pMHCI). The TCR/pMHCI interaction is pivotal in all aspects of CD8(+) T-cell immunity. However, the rules that govern the outcome of TCR/pMHCI engagement are not entirely understood, and this is a major barrier to understanding the requirements for both effective immunity and vaccination. In the present study, we discovered an unexpected feature of the TCR/pMHCI interaction by showing that any given TCR exhibits an explicit preference for a single MHCI-peptide length. Agonists of nonpreferred length were extremely rare, suboptimal, and often entirely distinct in sequence. Structural analysis indicated that alterations in peptide length have a major impact on antigenic complexity, to which individual TCRs are unable to adapt. This novel finding demonstrates that the outcome of TCR/pMHCI engagement is determined by peptide length in addition to the sequence identity of the MHCI-bound peptide. Accordingly, the effective recognition of pMHCI Ag, which is a prerequisite for successful CD8(+) T-cell immunity and protective vaccination, can only be achieved by length-matched Ag-specific CD8(+) T-cell clonotypes.
Original languageEnglish
Pages (from-to)1112-1123
Number of pages12
JournalBlood
Volume121
Issue number7
Early online date18 Dec 2012
DOIs
Publication statusPublished - 14 Feb 2013

Keywords

  • Clone Cells
  • Antigen Presentation
  • Peptide Library
  • Models, Molecular
  • Histocompatibility Antigens Class I
  • Humans
  • Receptors, Antigen, T-Cell, alpha-beta
  • Amino Acid Sequence
  • Peptide Fragments
  • Antigens
  • Immunity, Cellular
  • CD8-Positive T-Lymphocytes
  • Oligopeptides

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