ArticleThe Journal of biological chemistry2012
Interplay between T cell receptor binding kinetics and the level of cognate peptide presented by major histocompatibility complexes governs CD8+ T cell responsiveness.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed, 125 citations in OpenAlex.
- Selection of a Clinical Lead TCR Targeting Alpha-Fetoprotein-Positive Liver Cancer Based on a Balance of Risk and Benefit.Frontiers in immunology · 2020Trial
- Article
- A synthetic NKG2A engager enables long-term persistence of HLA-deficient allogeneic engineered Tregs.EMBO molecular medicine · 2026Article
- Predicting specificity of TCR-pMHC interactions using machine-learning and biophysical models.Cell systems · 2026Article
- A cell-based kinetic framework enables TCR specificity prediction.Signal transduction and targeted therapy · 2026Article
- Evaluating the effects of CD8/CD4 on T cell function in terms of TCR-pMHC-coreceptor catch and slip bonds.Frontiers in immunology · 2026Article
- A comparative mathematical modeling study of phenotypic approaches to T cell activation.Scientific reports · 2025Article
- Evaluating the effects of CD8/CD4 on T cell function in terms of TCR-pMHC-coreceptor catch and slip bonds.bioRxiv : the preprint server for biology · 2025Article
- APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence.Nature communications · 2025Article
- APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence.bioRxiv : the preprint server for biology · 2025Article
- Preclinical model for evaluating human TCRs against chimeric syngeneic tumors.Journal for immunotherapy of cancer · 2024Article
- Differential roles of kinetic on- and off-rates in T-cell receptor signal integration revealed with a modified Fab'-DNA ligand.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells.The Journal of clinical investigation · 2024Article
- Differential Roles of Kinetic On- and Off-Rates in T-Cell Receptor Signal Integration Revealed with a Modified Fab'-DNA Ligand.bioRxiv : the preprint server for biology · 2024Article
- Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria.Brain : a journal of neurology · 2024Article
- DGKα/ζ inhibition lowers the TCR affinity threshold and potentiates antitumor immunity.Science advances · 2023Article
- A lentiviral vector for the production of T cells with an inducible transgene and a constitutively expressed tumour-targeting receptor.Nature biomedical engineering · 2023Article
- Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors.Nature communications · 2023Article
- Large libraries of single-chain trimer peptide-MHCs enable antigen-specific CD8+ T cell discovery and analysis.Communications biology · 2023Article
- Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.Nature communications · 2023Article
27 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Through a rational design approach, we generated a panel of HLA-A*0201/NY-ESO-1(157-165)-specific T cell receptors (TCR) with increasing affinities of up to 150-fold from the wild-type TCR. Using these TCR variants which extend just beyond the natural affinity range, along with an extreme supraphysiologic one having 1400-fold enhanced affinity, and a low-binding one, we sought to determine the effect of TCR binding properties along with cognate peptide concentration on CD8(+) T cell responsiveness. Major histocompatibility complexes (MHC) expressed on the surface of various antigen presenting cells were peptide-pulsed and used to stimulate human CD8(+) T cells expressing the different TCR via lentiviral transduction. At intermediate peptide concentration we measured maximum cytokine/chemokine secretion, cytotoxicity, and Ca(2+) flux for CD8(+) T cells expressing TCR within a dissociation constant (K(D)) range of ∼1-5 μM. Under these same conditions there was a gradual attenuation in activity for supraphysiologic affinity TCR with K(D) < ∼1 μM, irrespective of CD8 co-engagement and of half-life (t(1/2) = ln 2/k(off)) values. With increased peptide concentration, however, the activity levels of CD8(+) T cells expressing supraphysiologic affinity TCR were gradually restored. Together our data support the productive hit rate model of T cell activation arguing that it is not the absolute number of TCR/pMHC complexes formed at equilibrium, but rather their productive turnover, that controls levels of biological activity. Our findings have important implications for various immunotherapies under development such as adoptive cell transfer of TCR-engineered CD8(+) T cells, as well as for peptide vaccination strategies.
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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.