A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists.

T lymphocyte activation is mediated by the interaction of specific TCR with antigenic peptides bound to MHC molecules. Single amino acid substitutions are often capable of changing the effect of a peptide from stimulatory to antagonistic. Using surface plasmon resonance, we have analyzed the interaction between a complex consisting of variants of the MCC peptide bound to a mouse class II MHC (Ek) and a specific TCR. Using both an improved direct binding method as well as a novel inhibition assay, we show that the affinities of three different antagonist peptide-Ek complexes are approximately 10-50 times lower than that of the wildtype MCC-Ek complex for the TCR, largely due to an increased off-rate. These results suggest that the biological effects of peptide antagonists and partial agonists may be largely based on kinetic parameters.

• Publication year

  1996

• Venue

  Immunity

• Publication date

  1996-07-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/S1074-7613(00)80309-XPMID 8758894
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Kinetic discrimination in T-cell activation.

  1996cited by this paper
• Essential flexibility in the T-cell recognition of antigen

  1996cited by this paper
• A surface plasmon resonance assay for the binding of influenza virus hemagglutinin to its sialic acid receptor.

  1996cited by this paper
• Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology.

  1996cited by this paper
• Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists

  1995cited by this paper
• Involvement of both major histocompatibility complex class II alpha and beta chains in CD4 function indicates a role for ordered oligomerization in T cell activation

  1995cited by this paper
• Serial triggering of many T-cell receptors by a few peptide–MHC complexes

  1995cited by this paper
• Kinetic proofreading in T-cell receptor signal transduction.

  1995cited by this paper
• Crystal structure of the beta chain of a T cell antigen receptor.

  1995cited by this paper
• Lack of strict correlation of functional sensitization with the apparent affinity of MHC/peptide complexes for the TCR.

  1995cited by this paper
• T cell receptor antagonists and partial agonists.

  1995cited by this paper
• Partial T cell signaling: altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy.

  1994cited by this paper
• The nature of major histocompatibility complex recognition by gamma delta T cells.

  1994cited by this paper
• A peptide antigen antagonist prevents the differentiation of T cell receptor transgenic thymocytes.

  1994cited by this paper
• Use of global amino acid replacements to define the requirements for MHC binding and T cell recognition of moth cytochrome c (93-103).

  1994influential reference
• Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness.

  1994influential reference
• Real-time competitive kinetic analysis of interactions between low-molecular-weight ligands in solution and surface-immobilized receptors.

  1994influential reference
• Human cell-adhesion molecule CD2 binds CD58 (LFA-3) with a very low affinity and an extremely fast dissociation rate but does not bind CD48 or CD59.

  1994cited by this paper
• Kinetics and affinity of reactions between an antigen-specific T cell receptor and peptide-MHC complexes.

  1994cited by this paper
• Antigen analogs/MHC complexes as specific T cell receptor antagonists.

  1994cited by this paper
• Both high and low avidity antibodies to the T cell receptor can have agonist or antagonist activity.

  1994cited by this paper
• T cell receptor-MHC class I peptide interactions: affinity, kinetics, and specificity.

  1994cited by this paper
• Negative selection of CD4+ CD8+ thymocytes by T-cell receptor peptide antagonists.

  1994cited by this paper
• High-affinity reactions between antigen-specific T-cell receptors and peptides associated with allogeneic and syngeneic major histocompatibility complex class I proteins.

  1994cited by this paper
• Partial T cell signaling: Altered phospho-ζ and lack of zap70 recruitment in APL-induced T cell anergy

  1994cited by this paper
• The nature of major histocompatibility complex recognition by γδ T cells

  1994cited by this paper
• Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1

  1993cited by this paper
• Direct detection of major histocompatibility complex class I binding to antigenic peptides using surface plasmon resonance. Peptide immobilization and characterization of binding specificity.

  1993cited by this paper
• Quantitative determination of surface concentration of protein with surface plasmon resonance using radiolabeled proteins

  1991cited by this paper
• Expression of a class II major histocompatibility complex (MHC) heterodimer in a lipid-linked form with enhanced peptide/soluble MHC complex formation at low pH

  1991cited by this paper
• Expression of T cell antigen receptor heterodimers in a lipid-linked form.

  1990cited by this paper
• Solid-phase binding of class I and II MHC proteins: immunoassay and T cell recognition.

  1989cited by this paper
• Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors.

  1989cited by this paper
• Ligand dissociation constants from competition binding assays: errors associated with ligand depletion.

  1987cited by this paper
• Isolation and characterization of antigen-Ia complexes involved in T cell recognition.

  1986cited by this paper
• The Fine Specificity of Antigen and la Determinant Recognition by T Cell Hybridoma Clones Specific for Pigeon Cytochrome c

  1982cited by this paper
• Continuous proliferation of murine antigen-specific helper T lymphocytes in culture

  1979cited by this paper
• Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction.

  1973cited by this paper

• Murine T-cell receptor OT-I exhibits imperfect discrimination between foreign and self-antigens

  2025cites this paper
• Regulatory T cells define affinity thresholds for CD8+ T cell tumor infiltration

  2025cites this paper
• T cell costimulatory and inhibitory signals di4erentially modulate LAT condensate nucleation propensity after TCR ligation

  2025cites this paper
• Kinetic Proofreading through Parallel Reactions on a Single T Cell Receptor

  2025cites this paper
• Parallel reactions on a single T cell receptor offer a robust kinetic proofreading mechanism

  2025cites this paper
• Using In silico models to predict lymphocyte activation and development in a data rich era.

  2024cites this paper
• Mechanical regulation of lymphocyte activation and function.

  2024cites this paper
• Antigen perception in T cells by long-term Erk and NFAT signaling dynamics

  2023cites this paper
• Modulation of antigen discrimination by duration of immune contacts in a kinetic proofreading model of T cell activation with extreme statistics

  2023cites this paper
• Antigen perception in T cells by long-term Erk and NFAT signaling dynamics

  2023cites this paper
• APLs and Oranges: Induction of T Cell Anergy by Altered Peptide Ligands.

  2023cites this paper
• T cells use distinct topographical and membrane receptor scanning strategies that individually coalesce during receptor recognition

  2022cites this paper
• A bead-based method for high-throughput mapping of the sequence- and force-dependence of T cell activation

  2022cites this paper
• The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering

  2022cites this paper
• A MICROFLUIDICS-BASED APPROACH FOR ISOLATION OF ANTIGEN-SPECIFIC CD8+ T CELLS

  2022cites this paper
• Mechanotransduction as a major driver of cell behaviour: mechanisms, and relevance to cell organization and future research

  2021cites this paper
• Cross-TCR Antagonism Revealed by Optogenetically Tuning the Half-Life of the TCR Ligand Binding

  2021cites this paper
• Discrete LAT condensates encode antigen information from single pMHC:TCR binding events

  2021cites this paper
• Structure-activity mapping of the peptide- and force-dependent landscape of T-cell activation

  2021cites this paper
• How a Proposed Hypothesis during My PhD Training Shaped My Career.

  2020cites this paper
• T cells exhibit unexpectedly low discriminatory power and can respond to ultra-low affinity peptide-MHC ligands

  2020cites this paper
• Future molecular medicine from white frangipani (Plumeria alba L.): A review

  2020cites this paper
• Relationship of 2D Affinity to T Cell Functional Outcomes

  2020cites this paper
• ImmunoPhysics and ImmunoEngineering

  2020cites this paper
• Optogenetic Tuning of Ligand Binding to The Human T cell Receptor Using The opto-ligand-TCR System

  2020cites this paper
• The discriminatory power of the T cell receptor

  2020cites this paper
• Mechanical Proofreading: A General Mechanism to Enhance the Fidelity of Information Transfer Between Cells

  2019cites this paper
• Structure-Guided T Cell Receptor Mutations that Alter Antigen Specificity, Cross-Reactivity, and Polyfunctional Phenotypes in Gene-Modified T Cells

  2019cites this paper
• How does T cell receptor clustering impact on signal transduction?

  2019cites this paper
• TCR–pMHC kinetics under force in a cell-free system show no intrinsic catch bond, but a minimal encounter duration before binding

  2019cites this paper
• Peptides in immunoengineering

  2018cites this paper
• Übertragung des koff-rate-Assays an CD8+ zytotoxischen T-Zellen vom murinen auf das humane System

  2018influential citation
• COMPARISON OF A DUAL STRATEGY FOR T-CELL ACTIVATION UNDER INHIBITION OF THE CD4 RECEPTOR

  2018cites this paper
• The avidity of cross-reactive virus-specific T cells for their viral and allogeneic epitopes is variable and depends on epitope expression.

  2018cites this paper
• Design strategies for new drugs targeting multicomponent systems : focusing on class II MHC proteins and acetylcholinesterase

  2017cites this paper
• Infectious pathogens may trigger specific allo-HLA reactivity via multiple mechanisms

  2017cites this paper
• Binding to MHC Interaction Recruits CD8 in Absence of High Affinity Xenoreactive TCR:MHC

  2017cites this paper
• Early T cell receptor signals globally modulate ligand:receptor affinities during antigen discrimination

  2017cites this paper
• the Quality of Early Signaling Events in Human T Thresholds for Effector Function Elicitation, and Relationships Among TCR Ligand Potency,

  2017cites this paper
• Visualizing dynamic microvillar search and stabilization during ligand detection by T cells

  2017cites this paper
• Energetic and flexibility properties captured by long molecular dynamics simulations of a membrane-embedded pMHCII-TCR complex.

  2016cites this paper
• Signaling of the T Cell Costimulatory Receptor CD28: Regulation and Initiation

  2016cites this paper
• Functional Consequences of CD4+ T Cell Receptor Ligation in the Immune Response to Listeria monocytogenes

  2015cites this paper
• Pillars article: The immunological synapse: a molecular machine controlling T cell activation. Science. 1999. 285: 221-227.

  2015cites this paper
• Experimental and theoretical bases for mechanisms of antigen discrimination by T cells

  2015cites this paper
• NK cells: tuned by peptide?

  2015cites this paper
• Incorporating Binding Kinetics in Drug Design

  2015cites this paper
• Understanding the structural dynamics of TCR-pMHC complex interactions.

  2014cites this paper
• Phenotypic models of T cell activation

  2014cites this paper
• 2D TCR–pMHC–CD8 kinetics determines T‐cell responses in a self‐antigen‐specific TCR system

  2014cites this paper
• Kinetic and Thermodynamic Rationale for SAHA Being a Preferential Human HDAC8 Inhibitor as Compared to the Structurally Similar Ligand, TSA

  2014cites this paper
• Molecular simulation of drug-binding kinetics

  2014cites this paper
• TCR Affinity Associated with Functional Differences between Dominant and Subdominant SIV Epitope-Specific CD8+ T Cells in Mamu-A*01 + Rhesus Monkeys

  2014cites this paper
• The Immunological Synapse

  2014cites this paper
• Organizing MHC Class II Presentation

  2014cites this paper
• Kinetic and thermodynamic rationale for suberoylanilide hydroxamic acid being a preferential human histone deacetylase 8 inhibitor as compared to the structurally similar ligand, trichostatin a.

  2013cites this paper
• A peptide's perspective on antigen presentation to the immune system.

  2013cites this paper
• The actin‐driven spatiotemporal organization of T‐cell signaling at the system scale

  2013cites this paper
• TCR signalling in response to affinity stimulation

  2013cites this paper
• Rate Dissociation TCR-Peptide/MHC Affinity, Not CD8+ T Cell Activation Is Governed by

  2013cites this paper
• Evolving immune circuits are generated by flexible, motile, and sequential immunological synapses

  2013cites this paper
• Monitoring the Dynamics of T Cell Clonal Diversity Using Recombinant Peptide:MHC Technology

  2013cites this paper
• The interdisciplinary science of T-cell recognition.

  2013cites this paper
• Negative Signal Model for TCR Antagonism Cutting Edge: A Test of the Dominant

  2013cites this paper
• with productive immune synapses A ligand-induced conformational change in the T cell receptor associated

  2013cites this paper
• Insights from in situ analysis of TCR–pMHC recognition: response of an interaction network

  2013cites this paper
• Transcription in Naive CD4+ T Cells Regulates NFATc/p Activity and Early IL-4 The Potency of TCR Signaling Differentially

  2013cites this paper
• Correlates with Thymocyte Selection Degree of TCR Internalization and Ca2+ Flux

  2013cites this paper
• Subtle changes in TCRα CDR1 profoundly increase the sensitivity of CD4 T cells.

  2013cites this paper
• Inflammatory T Cells Activation and Clonal Expansion of Central Role of Thrombospondin-1 in the

  2013cites this paper
• TCR-Ligand koff Rate Correlates with the Protective Capacity of Antigen-Specific CD8+ T Cells for Adoptive Transfer

  2013cites this paper
• IL-4 and IL-13 mediated down-regulation of CD8 expression levels can dampen anti-viral CD8⁺ T cell avidity following HIV-1 recombinant pox viral vaccination.

  2013cites this paper
• of Agonist Ligands Induction of T Cell Anergy by Low Numbers

  2013cites this paper
• α Cytokine Polarization by V Mechanisms for Glycolipid Antigen-Driven

  2013cites this paper
• HMG- CoA Reductase Inhibitors as Immunomodulators

  2012cites this paper
• Structural and biophysical determinants of αβ T‐cell antigen recognition

  2012cites this paper
• T cell antigen recognition at the cell membrane.

  2012influential citation
• Advances in Direct T‐Cell Alloreactivity: Function, Avidity, Biophysics and Structure

  2012cites this paper
• T cell triggering: insights from 2D kinetics analysis of molecular interactions

  2012cites this paper
• Caractérisation de l'activité fonctionnelle et métabolique des cellules NK en situation de stress nutritionnels : approche expérimentale in vitro et in vivo

  2012cites this paper
• Human Antitumor CD8+ T Cells Producing Th1 Polycytokines Show Superior Antigen Sensitivity and Tumor Recognition

  2012cites this paper
• Dynamic in situ cytometry uncovers T cell receptor signaling during immunological synapses and kinapses in vivo.

  2012cites this paper
• A stochastic T cell response criterion

  2012cites this paper
• ubtle changes in TCR CDR 1 profoundly increase the sensitivity of CD 4 T cells

  2012cites this paper
• Characterization Of The Mamu-A*01-Restricted Cd8-Positive T Lymphocyte Immunodominance Hierarchy In Simian Immunodeficiency Virus-Infected Rhesus Monkeys

  2012influential citation
• Development of a novel TCR avidity assay for human CD8+ T cells

  2012cites this paper
• The dependence of CD4 T cell development and activation on the kinetics of the TCR:pMHC interaction

  2012cites this paper
• Structural Basis of Specificity and Cross-Reactivity in T Cell Receptors Specific for Cytochrome c–I-Ek

  2011cites this paper
• Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling

  2011influential citation
• Epitope Peptide:MHC Class I Binding TCR:Epitope Peptide Affinity but not Simian Immunodeficiency Virus Diminish Mutations in a Dominant Nef Epitope of

  2011cites this paper
• Design of Glycopeptides Used to Investigate Class II MHC Binding and T-Cell Responses Associated with Autoimmune Arthritis

  2011cites this paper
• Mechanisms controlling granule-mediated cytolytic activity of cytotoxic T lymphocytes

  2011cites this paper
• (E)-alkene and ethylene isosteres substantially alter the hydrogen-bonding network in class II MHC A(q)/glycopeptide complexes and affect T-cell recognition.

  2011cites this paper
• Advances in Direct T-Cell Alloreactivity : Function , Avidity , Biophysics and Structure

  2011cites this paper
• Immunological perspective of self versus tumor antigens: insights from the RIP‐gp model

  2011cites this paper
• CD4+ T cell interactions through CD28/B7 molecules affects their Th1/Th2 phenotype

  2011cites this paper
• Modified Glycopeptides Targeting Rheumatoid Arthritis : Exploring molecular interactions in class II MHC/glycopeptide/T-cell receptor complexes

  2011cites this paper
• Mutations in a Dominant Nef Epitope of Simian Immunodeficiency Virus Diminish TCR:Epitope Peptide Affinity but not Epitope Peptide:MHC Class I Binding

  2011cites this paper
• Creation of lysine-deficient mutant lymphotoxin-alpha with receptor selectivity by using a phage display system.

  2010cites this paper
• MM–GBSA binding free energy decomposition and T cell receptor engineering

  2010cites this paper