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Structural Mechanism Underpinning Cross-reactivity of a CD8 + T-cell Clone That Recognizes a Peptide Derived from Human Telomerase Reverse Transcriptase

DOI: 10.1074/jbc.M116.741603 DOI Help

Authors: David K. Cole (Cardiff University School of Medicine) , Hugo A. Van Den Berg (University of Warwick) , Angharad Lloyd (Cardiff University) , Michael D. Crowther (Cardiff University) , Konrad Beck (Cardiff University School of Dentistry) , Julia Ekeruche-makinde (Cardiff University School of Medicine) , John J. Miles (Cardiff University School of Medicine; Queensland Institute of Medical Research Berghofer Medical Research Institute; James Cook University, Australia) , Anna M. Bulek (Cardiff University School of Medicine) , Garry Dolton (Cardiff University School of Medicine) , Andrea J. Schauenburg (Cardiff University School of Medicine) , Aaron Wall (Cardiff University School of Medicine) , Anna Fuller (Cardiff University School of Medicine) , Mathew Clement (Cardiff University School of Medicine) , Bruno Laugel (Cardiff University School of Medicine) , Pierre J. Rizkallah (Cardiff University School of Medicine) , Linda Wooldridge (Cardiff University School of Medicine) , Andrew K. Sewell (Cardiff University School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 292 , PAGES 802 - 813

State: Published (Approved)
Published: January 2017
Diamond Proposal Number(s): 6232 , 8096 , 10462 , 10049 , 9308 , 12332

Open Access Open Access

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 focused 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. The ILA1 TCR contacted its pMHC with a broad peptide binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide 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 cross-reactivity with important implications for pathogen surveillance, autoimmunity, and transplant rejection.

Journal Keywords: peptides; surface plasmon resonance (SPR); telomerase; tumor immunology; X-ray crystallography; T cell receptor; T cell degeneracy; T cells

Subject Areas: Medicine, Biology and Bio-materials

Instruments: B23-Circular Dichroism , I02-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: No


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