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Structural basis for ineffective T-cell responses to MHC anchor residue-improved 'heteroclitic' peptides

Madura, Florian, Rizkallah, Pierre ORCID:, Holland, Christopher J., Fuller, Anna, Bulek, Anna Marta, Godkin, Andrew James ORCID:, Schauenburg, Andrea J., Cole, David K. ORCID: and Sewell, Andrew K. ORCID: 2015. Structural basis for ineffective T-cell responses to MHC anchor residue-improved 'heteroclitic' peptides. European Journal of Immunology 45 (2) , pp. 584-591. 10.1002/eji.201445114

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MHC anchor residue-modified “heteroclitic” peptides have been used in many cancer vaccine trials and often induce greater immune responses than the wild-type peptide. The best-studied system to date is the decamer MART-1/Melan-A26–35 peptide, EAAGIGILTV, where the natural alanine at position 2 has been modified to leucine to improve human leukocyte antigen (HLA)-A*0201 anchoring. The resulting ELAGIGILTV peptide has been used in many studies. We recently showed that T cells primed with the ELAGIGILTV peptide can fail to recognize the natural tumor-expressed peptide efficiently, thereby providing a potential molecular reason for why clinical trials of this peptide have been unsuccessful. Here, we solved the structure of a TCR in complex with HLA-A*0201-EAAGIGILTV peptide and compared it with its heteroclitic counterpart , HLA-A*0201-ELAGIGILTV. The data demonstrate that a suboptimal anchor residue at position 2 enables the TCR to “pull” the peptide away from the MHC binding groove, facilitating extra contacts with both the peptide and MHC surface. These data explain how a TCR can distinguish between two epitopes that differ by only a single MHC anchor residue and demonstrate how weak MHC anchoring can enable an induced-fit interaction with the TCR. Our findings constitute a novel demonstration of the extreme sensitivity of the TCR to minor alterations in peptide conformation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Additional Information: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Publisher: Wiley
ISSN: 0014-2980
Funders: BBSRC, Wellcome Trust
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 26 November 2014
Last Modified: 06 Jul 2023 00:19

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