Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 45, Issue 2, Pages 584-591Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.201445114
Keywords
Cross-reactivity; Crystal structure; MART-1; Melan-A; Melanoma; Peptide-major histocompatibility complex; Surface plasmon resonance; T-cell; TCR
Categories
Funding
- Tenovus PhD studentship
- UK Biotechnology and Biological Sciences Research Council [BB/H001085/1]
- RCUK
- BBSRC [BB/H001085/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H001085/1] Funding Source: researchfish
- Tenovus Cancer Care [PhD2009/L20] Funding Source: researchfish
- Wellcome Trust [100327/Z/12/Z] Funding Source: researchfish
- Wellcome Trust [100327/Z/12/Z] Funding Source: Wellcome Trust
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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.
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