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

DOI: 10.1002/eji.201445114 DOI Help
PMID: 25471691 PMID Help

Authors: Florian Madura (Cardiff University) , Pierre Rizkallah (Cardiff University) , Christopher J. Holland (Cardiff University School of Medicine) , Anna Fuller (Cardiff University School of Medicine) , Anna Bulek (Cardiff University School of Medicine) , Andrew J Godkin (Cardiff University School of Medicine) , Andrea J. Schauenburg (Cardiff University School of Medicine) , David K. Cole (Cardiff University School of Medicine) , Andrew K. Sewell (Cardiff University School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Immunology

State: Published (Approved)
Published: December 2014

Open Access Open Access

Abstract: 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.

Subject Areas: Biology and Bio-materials

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 19/12/2014 00:22

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