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

Authors :
Madura, Florian
Rizkallah, Pierre J.
Holland, Christopher J.
Fuller, Anna
Bulek, Anna
Godkin, Andrew J.
Schauenburg, Andrea J.
Cole, David K.
Sewell, Andrew K.
Source :
European Journal of Immunology; Feb2015, Vol. 45 Issue 2, p584-591, 8p
Publication Year :
2015

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-A<subscript>26-35</subscript> 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 E LAGIGILTV peptide has been used in many studies. We recently showed that T cells primed with the E LAGIGILTV 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-E LAGIGILTV. 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00142980
Volume :
45
Issue :
2
Database :
Complementary Index
Journal :
European Journal of Immunology
Publication Type :
Academic Journal
Accession number :
100883565
Full Text :
https://doi.org/10.1002/eji.201445114