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

Cole, David K. ORCID: https://orcid.org/0000-0003-0028-9396, van den Berg, Hugo A., Lloyd, Angharad, Crowther, Michael D., Beck, Konrad ORCID: https://orcid.org/0000-0001-5098-9484, Ekeruche-Makinde, Julia, Miles, John J., Bulek, Anna M., Dolton, Garry, Schauenburg, Andrea J., Wall, Aaron, Fuller, Anna, Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, Laugel, Bruno, Rizkallah, Pierre J. ORCID: https://orcid.org/0000-0002-9290-0369, Wooldridge, Linda and Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 2017. Structural mechanism underpinning cross-reactivity of a CD8+ T-cell clone that recognises a peptide derived from human telomerase reverse transcriptase. Journal of Biological Chemistry 292 (3) , pp. 802-813. 10.1074/jbc.M116.741603

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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 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry Medicine
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	peptides surface plasmon resonance (SPR) telomerase tumor immunology X-ray crystallography T cell receptor T-cell degeneracy t cells
Additional Information:	This is an open access article under the CC BY license.
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Funders:	Wellcome Trust
Date of First Compliant Deposit:	19 December 2016
Date of Acceptance:	30 November 2016
Last Modified:	05 Jan 2024 08:15
URI:	https://orca.cardiff.ac.uk/id/eprint/96986

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