ArticleEuropean journal of immunology2015
Structural basis for ineffective T-cell responses to MHC anchor residue-improved "heteroclitic" peptides.
Article in European journal of immunology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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47 citing papers in PubMed, 69 citations in OpenAlex.
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- HLA A*24:02-restricted T cell receptors cross-recognize bacterial and preproinsulin peptides in type 1 diabetes.The Journal of clinical investigation · 2024Article
- Defining and Studying B Cell Receptor and TCR Interactions.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM.Nature communications · 2023Article
- Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes.Frontiers in immunology · 2023Article
- Peptide-based vaccine for cancer therapies.Frontiers in immunology · 2023Review
- Therapeutic high affinity T cell receptor targeting a KRASNature communications · 2022Article
- Structure-guided stabilization of pathogen-derived peptide-HLA-E complexes using non-natural amino acids conserves native TCR recognition.European journal of immunology · 2022Article
- Unconventional modes of peptide-HLA-I presentation change the rules of TCR engagement.Discovery immunology · 2022Review
- CD8 T cell function and cross-reactivity explored by stepwise increased peptide-HLA versus TCR affinity.Frontiers in immunology · 2022Article
- Synthetic Peptides with Inadvertent Chemical Modifications Can Activate Potentially Autoreactive T Cells.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
- Tumor rejection properties of gp100Molecular immunology · 2021Article
- Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Characterization of amino acid residues of T-cell receptors interacting with HLA-A*02-restricted antigen peptides.Annals of translational medicine · 2021Article
- Identification and characterization of heteroclitic peptides in TCR-binding positions with improved HLA-binding efficacy.Journal of translational medicine · 2021Article
- Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Contribution of T Cell Receptor Alpha and Beta CDR3, MHC Typing, V and J Genes to Peptide Binding Prediction.Frontiers in immunology · 2021Article
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9 authors at 1 institution in 1 country.
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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.
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