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A molecular switch in immunodominant HIV-1-specific CD8 T-cell epitopes shapes differential HLA-restricted escape
DOI:
10.1186/s12977-015-0149-5
PMID:
25808313
Authors:
Henrik N
Kløverpris
(University of KwaZulu-Natal)
,
David
Cole
(Cardiff University)
,
Anna
Fuller
(Cardiff University)
,
Jonathan
Carlson
(Microsoft Research eScience Group, Los Angeles)
,
Konrad
Beck
(Cardiff University School of Dentistry)
,
Andrea
Schauenburg
(Cardiff University)
,
Pierre
Rizkallah
(Cardiff University)
,
Søren
Buus
(University of Copenhagen)
,
Andrew K
Sewell
(Cardiff University School of Medicine)
,
Philip
Goulder
(University of Oxford)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Retrovirology
, VOL 12
State:
Published (Approved)
Published:
February 2015
Diamond Proposal Number(s):
8096
Open Access
Abstract: 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-A2635 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 singleMHC anchor residue and demonstrate how weakMHC 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:
Medicine,
Biology and Bio-materials
Instruments:
I04-1-Macromolecular Crystallography (fixed wavelength)
Other Facilities: No
Discipline Tags:
Technical Tags: