Structural mechanism underpinning cross-reactivity of a CD8+ T-cell clone that recognises a peptide derived from human telomerase reverse transcriptase

David K Cole, Linda Wooldridge, Andrew K Sewell

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

11 Citations (Scopus)
256 Downloads (Pure)

Abstract

T-cell cross-reactivity is essential for effective immune surveillance, but has also
been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focussed antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage
with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase (hTERT). The ILA1 TCR contacted its pMHC with a broad peptide-binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCRpeptide
binding , the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide
contacts apparent in the structure correlated well with the level of degeneracy at different peptide positions. Thus, the ILA1 TCR was less tolerant of changes at peptide residues that were at, or adjacent to, key contact sites. This study provides new insights into the molecular mechanisms that control T-cell crossreactivity, with important implications for pathogen surveillance, autoimmunity and transplant rejection.
Original languageEnglish
Pages (from-to)802-813
Number of pages12
JournalJournal of Biological Chemistry
Volume292
Early online date1 Dec 2016
DOIs
Publication statusPublished - 20 Jan 2017

Keywords

  • CD8+ T-cells
  • T-cell receptor (TCR)
  • peptide-major histocompatibility complex (pMHC)
  • T-cell degeneracy
  • telomerase
  • surface plasmon resonance
  • X-ray crystallography

Fingerprint Dive into the research topics of 'Structural mechanism underpinning cross-reactivity of a CD8+ T-cell clone that recognises a peptide derived from human telomerase reverse transcriptase'. Together they form a unique fingerprint.

Cite this