ArticleProceedings of the National Academy of Sciences of the United States of America2012
Structural insights into the editing of germ-line-encoded interactions between T-cell receptor and MHC class II by Vα CDR3.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 45 citations in OpenAlex.
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- Structural basis for T cell recognition of cancer neoantigens and implications for predicting neoepitope immunogenicity.Frontiers in immunology · 2023Review
- Naive and memory T cells TCR-HLA-binding prediction.Oxford open immunology · 2022Article
- Stereo electronic principles for selecting fully-protective, chemically-synthesised malaria vaccines.Frontiers in immunology · 2022Review
- T Cell Receptor Genotype andGenes · 2021Article
- The Many Faces of CD4International journal of molecular sciences · 2020Review
- CD4Cell reports · 2020Article
- MHC-II alleles shape the CDR3 repertoires of conventional and regulatory naïve CD4Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen.Nature communications · 2020Article
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- Structural basis for clonal diversity of the human T-cell response to a dominant influenza virus epitope.The Journal of biological chemistry · 2017Article
- Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes.Journal of immunology (Baltimore, Md. : 1950) · 2017Review
- Conserved Vδ1 Binding Geometry in a Setting of Locus-Disparate pHLA Recognition by δ/αβ T Cell Receptors (TCRs): Insight into Recognition of HIV Peptides by TCRs.Journal of virology · 2017Article
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- Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity.The Journal of clinical investigation · 2016Article
- Differential utilization of binding loop flexibility in T cell receptor ligand selection and cross-reactivity.Scientific reports · 2016Article
- How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity.Nature immunology · 2016Article
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Authors and funding
5 authors at 4 institutions in 1 country.
Funding
Abstract
The conserved diagonal docking mode observed in structures of T-cell receptors (TCRs) bound to peptide-MHC ligands is believed to reflect coevolution of TCR and MHC genes. This coevolution is supported by the conservation of certain interactions between the germ-line-encoded complementarity-determining region (CDR)1 and CDR2 loops of TCR and MHC. However, the rules governing these interactions are not straightforward, even when the same variable (V) region recognizes the same MHC molecule. Here, we demonstrate that the somatically generated CDR3 loops can markedly alter evolutionarily selected contacts between TCR and MHC ("CDR3 editing"). To understand CDR3 editing at the atomic level, we determined the structure of a human melanoma-specific TCR (G4) bound to the MHC class II molecule HLA-DR1 and an epitope from mutant triose phosphate isomerase (mutTPI). A comparison of the G4-mutTPI-DR1 complex with a complex involving a TCR (E8) that uses the same Vα region to recognize the same mutTPI-DR1 ligand as G4 revealed that CDR1α adopts markedly different conformations in the two TCRs, resulting in an almost entirely different set of contacts with MHC. Based on the structures of unbound G4 and E8, the distinct conformations of CDR1α in these TCRs are not induced by binding to mutTPI-DR1 but result from differences in the length and sequence of CDR3α that are transmitted to CDR1α. The editing of germ-line-encoded TCR-MHC interactions by CDR3 demonstrates that these interactions possess sufficient intrinsic flexibility to accommodate large structural variations in CDR3 and, consequently, in the TCR-binding site.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.