NDLI: Structural basis for ineffective T-cell responses to MHC anchor residue-improved “heteroclitic” peptides

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Structural basis for ineffective T-cell responses to MHC anchor residue-improved “heteroclitic” peptides

Content Provider	Scilit
Author	Madura, Florian Rizkallah, Pierre J. Holland, Christopher J. Fuller, Anna Bulek, Anna Godkin, Andrew J. Schauenburg, Andrea J. Cole, David K. Sewell, Andrew K.
Copyright Year	2014
Description	Journal: European Journal of Immunology 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)-A0201 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-A0201-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.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357396/pdf
Ending Page	591
Page Count	8
Starting Page	584
e-ISSN	15214141
DOI	10.1002/eji.201445114
Journal	European Journal of Immunology
Issue Number	2
Volume Number	45
Language	English
Publisher	Wiley-Blackwell
Publisher Date	2014-12-28
Access Restriction	Open
Subject Keyword	Journal: European Journal of Immunology Biochemistry and Molecular Biology Crystal Structure Peptide-major Histocompatibility Complex Surface Plasmon Resonance
Content Type	Text

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