T Cell Cross-Reactivity and Conformational Changes during TCR Engagement

All thymically selected T cells are inherently cross-reactive, yet many data indicate a fine specificity in antigen recognition, which enables virus escape from immune control by mutation in infections such as the human immunodeficiency virus (HIV). To address this paradox, we analyzed the fine specificity of T cells recognizing a human histocompatibility leukocyte antigen (HLA)-A2–restricted, strongly immunodominant, HIV gag epitope (SLFNTVATL). The majority of 171 variant peptides tested bound HLA-A2, but only one third were recognized. Surprisingly, one recognized variant (SLYNTVATL) showed marked differences in structure when bound to HLA-A2. T cell receptor (TCR) recognition of variants of these two peptides implied that they adopted the same conformation in the TCR–peptide–major histocompatibility complex (MHC) complex. However, the on-rate kinetics of TCR binding were identical, implying that conformational changes at the TCR–peptide–MHC binding interface occur after an initial permissive antigen contact. These findings have implications for the rational design of vaccines targeting viruses with unstable genomes.

• Publication year

  2004

• Venue

  Journal of Experimental Medicine

• Publication date

  2004-12-06

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/jem.20041251PMID 15583017PMCID 2211951
• 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.

• Conformational changes associated with protein-protein interactions.

  2004cited by this paper
• T cell receptor-ligand interactions: A conformational preequilibrium or an induced fit

  2004cited by this paper
• Molecular interactions mediating T cell antigen recognition.

  2003cited by this paper
• Distinct molecular mechanisms account for the specificity of two different T-cell receptors.

  2003cited by this paper
• CDR3 loop flexibility contributes to the degeneracy of TCR recognition

  2003cited by this paper
• A structural basis for immunodominant human T cell receptor recognition

  2003cited by this paper
• Evidence of HIV-1 Adaptation to HLA-Restricted Immune Responses at a Population Level

  2002cited by this paper
• Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes

  2002cited by this paper
• Two-step binding mechanism for T-cell receptor recognition of peptide–MHC

  2002influential reference
• A Novel Approach to the Analysis of Specificity, Clonality, and Frequency of HIV-Specific T Cell Responses Reveals a Potential Mechanism for Control of Viral Escape1

  2002cited by this paper
• A functional and structural basis for TCR cross-reactivity in multiple sclerosis

  2002cited by this paper
• The specificity of TCR/pMHC interaction.

  2002cited by this paper
• Opinion — vaccines: The quest for an AIDS vaccine: is the CD8+ T-cell approach feasible?

  2002cited by this paper
• Clinical trials of HIV vaccines.

  2002cited by this paper
• Reverse transcriptase template switching: a SMART approach for full-length cDNA library construction.

  2001cited by this paper
• T Cell Activity Correlates with Oligomeric Peptide-Major Histocompatibility Complex Binding on T Cell Surface*

  2001cited by this paper
• Substantial Differences in Specificity of HIV-Specific Cytotoxic T Cells in Acute and Chronic HIV Infection

  2001cited by this paper
• Crystal Structures of Two Closely Related but Antigenically Distinct HLA-A2/Melanocyte-Melanoma Tumor-Antigen Peptide Complexes1

  2001cited by this paper
• Crystal structure of a T cell receptor bound to an allogeneic MHC molecule

  2000cited by this paper
• Automated protein model building combined with iterative structure refinement

  1999cited by this paper
• TCR binding to peptide-MHC stabilizes a flexible recognition interface.

  1999influential reference
• Poor Binding of a HER-2/neu Epitope (GP2) to HLA-A2.1 Is due to a Lack of Interactions with the Center of the Peptide*

  1999cited by this paper
• Further additions to MolScript version 1.4, including reading and contouring of electron-density maps.

  1999cited by this paper
• Structural, biochemical, and biophysical studies of HLA-A2/altered peptide ligands binding to viral-peptide-specific human T-cell receptors.

  1999cited by this paper
• Peptide recognition by two HLA-A2/Tax11-19-specific T cell clones in relationship to their MHC/peptide/TCR crystal structures.

  1999cited by this paper
• Rapid automated molecular replacement by evolutionary search.

  1999cited by this paper
• Four A6-TCR/peptide/HLA-A2 structures that generate very different T cell signals are nearly identical.

  1999cited by this paper
• Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef

  1999cited by this paper
• A kinetic basis for T cell receptor repertoire selection during an immune response.

  1999cited by this paper
• Crystallography & NMR system: A new software suite for macromolecular structure determination.

  1998cited by this paper
• Cross‐clade recognition of p55 by cytotoxic T lymphocytes in HIV‐1 infection

  1998cited by this paper
• Cross-clade-specific cytotoxic T lymphocytes in HIV-1-infected children.

  1998cited by this paper
• A very high level of crossreactivity is an essential feature of the T-cell receptor.

  1998cited by this paper
• Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids.

  1998cited by this paper
• CD8 expression allows T cell signaling by monomeric peptide-MHC complexes.

  1998influential reference
• [20] Processing of X-ray diffraction data collected in oscillation mode.

  1997cited by this paper
• Escape of human immunodeficiency virus from immune control.

  1997cited by this paper
• Refinement of macromolecular structures by the maximum-likelihood method.

  1997cited by this paper
• Cross-clade human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte responses in HIV-infected Zambians

  1997cited by this paper
• Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection.

  1997cited by this paper
• Antiviral pressure exerted by HIV-l-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus

  1997cited by this paper
• Clade B-based HIV-1 vaccines elicit cross-clade cytotoxic T lymphocyte reactivities in uninfected volunteers.

  1997cited by this paper
• Processing of X-ray diffraction data collected in oscillation mode.

  1997cited by this paper
• Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS

  1997cited by this paper
• Cytotoxic T-lymphocyte cross-reactivity among different human immunodeficiency virus type 1 clades: implications for vaccine development

  1997cited by this paper
• Cross‐reactive memory T cells for Epstein‐Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex‐bound peptide by T cells and its role in alloreactivity

  1997cited by this paper
• An αβ T Cell Receptor Structure at 2.5 Å and Its Orientation in the TCR-MHC Complex

  1996cited by this paper
• Structure of the complex between human T-cell receptor, viral peptide and HLA-A2

  1996cited by this paper
• Response of Mycobacterium tuberculosis to Reactive Oxygen and Nitrogen Intermediates

  1996cited by this paper
• The repertoire of T cells shaped by a single MHC/peptide ligand.

  1996cited by this paper
• Rapid, electrostatically assisted association of proteins

  1996cited by this paper
• Antagonist HIV-1 Gag Peptides Induce Structural Changes in HLA B8

  1996cited by this paper
• Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response.

  1996cited by this paper
• T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen

  1995cited by this paper
• Induction of a primary human cytotoxic T‐lymphocyte response against a novel conserved epitope in a functional sequence of HIV‐1 reverse transcriptase

  1995cited by this paper
• Thermodynamic study of the pH-dependent interaction of chromogranin A with an intraluminal loop peptide of the inositol 1,4,5-trisphosphate receptor.

  1995cited by this paper
• Five viral peptide-HLA-A2 co-crystals. Simultaneous space group determination and X-ray data collection.

  1994cited by this paper
• Elements of Physical Chemistry

  1993cited by this paper
• The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2.

  1993influential reference
• Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition

  1991cited by this paper
• Kinetics and efficacy of positive selection in the thymus of normal and T cell receptor transgenic mice.

  1991cited by this paper
• Improved methods for building protein models in electron density maps and the location of errors in these models.

  1991cited by this paper
• Presentation of viral antigen controlled by a gene in the major histocompatibility complex

  1990cited by this paper
• Recognition of influenza A matrix protein by HLA-A2-restricted cytotoxic T lymphocytes. Use of analogues to orientate the matrix peptide in the HLA-A2 binding site

  1988cited by this paper
• The use of hydrophobic, alpha-helix-defined peptides in delineating the T cell determinant for pigeon cytochrome c.

  1987cited 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
• Crystal structure of cat muscle pyruvate kinase at a resolution of 2.6 A.

  1979cited by this paper
• Structural aspects of immune recognition of lysozymes. III. T cell specificity restriction and its consequences for antibody specificity

  1976cited by this paper
• Interactions Between Two Antigens Governed by the Poly-L-lysine Gene: Failure of One to Inhibit Competitively an in Vitro Response to the Other 1

  1974cited by this paper
• The Elements of Physical Chemistry

  year unknowncited by this paper

• Curation at Scale with EPITOME: Extraction Pipeline for Immunological Texts and Open-Source Multimodal Enquiry

  2026cites this paper
• Dynamical network analysis reveals long-range residue couplings at the pMHC interface underlying enhanced immunogenicity

  2026cites this paper
• From Structure to Immunogenicity: Decoding Correlated Dynamics at the Peptide MHC interface to Understand TCR Recognition

  2025cites this paper
• Within-host viral evolution varies with T cell receptor repertoire diversity independently of viral mutation rates

  2025cites this paper
• Effect of Binary Mechanical Environment on T Cell Function.

  2025cites this paper
• High TCR Degeneracy Enhances Antiviral Efficacy of HTLV-1-Specific CTLs by Targeting Variant Viruses in HAM Patients

  2025cites this paper
• A binary trait model reveals the fitness effects of HIV-1 escape from T cell responses

  2025cites this paper
• Efficient epistasis inference via higher-order covariance matrix factorization.

  2025cites this paper
• Enhanced T cell receptor specificity through framework engineering

  2024cites this paper
• A binary trait model reveals the fitness effects of HIV-1 escape from T cell responses

  2024cites this paper
• Asymmetric framework motion of TCRαβ controls load-dependent peptide discrimination

  2024cites this paper
• Unveiling cross-reactivity: implications for immune response modulation in cancer

  2024influential citation
• Efficient epistasis inference via higher-order covariance matrix factorization

  2024cites this paper
• Effect of the Environmental Mechanical Heterogeneity on T Cell Function

  2024cites this paper
• Asymmetric framework motion of TCRαβ controls load-dependent peptide discrimination

  2023cites this paper
• In Silico Analysis Predicts a Limited Impact of SARS-CoV-2 Variants on CD8 T Cell Recognition

  2022cites this paper
• Structural Prediction of Peptide-MHC Binding Modes.

  2022cites this paper
• Deconvoluting the T Cell Response to SARS-CoV-2: Specificity Versus Chance and Cognate Cross-Reactivity

  2021cites this paper
• Mechanobiology of T Cell Activation: To Catch a Bond.

  2021cites this paper
• A review on the effect of prolyl isomerization on immune response aberration and hypersensitivity reactions: A unifying hypothesis.

  2021cites this paper
• Molecular mechanism of the recognition of bacterially cleaved immunoglobulin by the immune regulatory receptor LILRA2

  2020cites this paper
• Deconvoluting the T cell response to SARS-CoV-2: specificity versus chance- and cognate cross-reactivity

  2020cites this paper
• Identifying the immune interactions underlying HLA class I disease associations

  2020cites this paper
• Heterologous immune responses in health and disease

  2020cites this paper
• POTN: A Human Leukocyte Antigen-A2 Immunogenic Peptides Screening Model and Its Applications in Tumor Antigens Prediction

  2020cites this paper
• Harnessing CD8+ T Cells Under HIV Antiretroviral Therapy

  2019cites this paper
• Mechanosensing through immunoreceptors

  2019cites this paper
• Intramolecular Domain Movements of Free and Bound pMHC and TCR Proteins: A Molecular Dynamics Simulation Study

  2019cites this paper
• Quantitative Prediction of the Landscape of T Cell Epitope Immunogenicity in Sequence Space

  2019influential citation
• Efficient Induction of T Cells against Conserved HIV-1 Regions by Mosaic Vaccines Delivered as Self-Amplifying mRNA

  2018cites this paper
• Computational Methods for Identification of T Cell Neoepitopes in Tumors.

  2018cites this paper
• The landscape of T cell epitope immunogenicity in sequence space

  2018cites this paper
• Facile method for screening clinical T cell receptors for off-target peptide-HLA reactivity

  2018cites this paper
• Previously Hidden Dynamics at the TCR–Peptide–MHC Interface Revealed

  2018influential citation
• Rational design of vaccine targets and strategies for HIV: a crossroad of statistical physics, biology, and medicine

  2017cites this paper
• Peptide and Peptide-Dependent Motions in MHC Proteins: Immunological Implications and Biophysical Underpinnings

  2017cites this paper
• Long-term follow up of human T-cell responses to conserved HIV-1 regions elicited by DNA/simian adenovirus/MVA vaccine regimens

  2017cites this paper
• Previously Hidden Dynamics at the TCR-pMHC Interface Revealed

  2017cites this paper
• Ex vivo Charakterisierung von humanen Autoantigen-spezifischen CD4+ T-Zellen mit Fokus auf Multiple Sklerose

  2017cites this paper
• Dual Molecular Mechanisms Govern Escape at Immunodominant HLA A2-Restricted HIV Epitope

  2017cites this paper
• The contribution of major histocompatibility complex contacts to the affinity and kinetics of T cell receptor binding

  2016cites this paper
• Increased Valency of Conserved-mosaic Vaccines Enhances the Breadth and Depth of Epitope Recognition.

  2016cites this paper
• Control of HIV-1 replication in vitro by vaccine-induced human CD8+ T cells through conserved subdominant Pol epitopes

  2016cites this paper
• CD8 T‐cell responses against the immunodominant Theileria parva peptide Tp249–59 are composed of two distinct populations specific for overlapping 11‐mer and 10‐mer epitopes

  2016cites this paper
• Action and Traction: Cytoskeletal Control of Receptor Triggering at the Immunological Synapse

  2016cites this paper
• Energetic and flexibility properties captured by long molecular dynamics simulations of a membrane-embedded pMHCII-TCR complex.

  2016cites this paper
• Broad HIV-1 inhibition in vitro by vaccine-elicited CD8+ T cells in African adults

  2016cites this paper
• Nationwide Trends in Molecular Epidemiology of HIV-1 in China

  2016cites this paper
• Relative rate and location of intra-host HIV evolution to evade cellular immunity are predictable

  2016cites this paper
• Theoretical Dynamics and Energetics of HLA-A2/SLYNTVATL Interaction

  2015influential citation
• HIV-1 vaccine immunogen design strategies

  2015cites this paper
• Immunotherapy of Prostate Carcinoma with biodegradable PLGA Microspheres

  2015cites this paper
• DockTope: a Web-based tool for automated pMHC-I modelling

  2015cites this paper
• Water dynamics at the MHCI-peptide binding interface studied by Hydrogen-deuterium exchange and structural studies of Apo A-I mimetic peptide-lipid binding

  2014influential citation
• Understanding the structural dynamics of TCR-pMHC complex interactions.

  2014cites this paper
• Conserved immunogens in prime-boost strategies for the next-generation HIV-1 vaccines

  2014cites this paper
• Vaccines that stimulate T cell immunity to HIV-1: the next step

  2014cites this paper
• Opposing actin networks modulate the mechano-activation of the integrin LFA-1 during immunological synapse formation

  2014cites this paper
• Altered Peptide Ligands Revisited: Vaccine Design through Chemically Modified HLA-A2–Restricted T Cell Epitopes

  2014cites this paper
• NetTepi: an integrated method for the prediction of T cell epitopes

  2014cites this paper
• Analysis of Relationships between Peptide/MHC Structural Features and Naive T Cell Frequency in Humans

  2014cites this paper
• Sulfamethoxazole Induces a Switch Mechanism in T Cell Receptors Containing TCRVβ20-1, Altering pHLA Recognition

  2013cites this paper
• Emerging concepts in immunity to hepatitis C virus infection.

  2013cites this paper
• Molecular monitoring of HIV-1 drug resistance in Ifakara HIV-1 Cohort, Tanzania

  2013cites this paper
• Individual MHCI-Restricted T-Cell Receptors are Characterized by a Unique Peptide Recognition Signature

  2013cites this paper
• Implications of HIV diversity for the HIV-1 pandemic.

  2013cites this paper
• Accurate structure prediction of peptide-MHC complexes for identifying highly immunogenic antigens.

  2013cites this paper
• Properties of MHC Class I Presented Peptides That Enhance Immunogenicity

  2013cites this paper
• Functional analysis of T cells lacking germline-encoded complementarity-determining regions

  2013cites this paper
• Estimating the Diversity, Completeness, and Cross-Reactivity of the T Cell Repertoire

  2013cites this paper
• CD8+ T Cell Cross-Reactivity Profiles and HIV-1 Immune Escape towards an HLA-B35-Restricted Immunodominant Nef Epitope

  2013cites this paper
• Méthode permettant de prédire la liaison non ciblée d'un peptide qui se lie à un peptide cible présenté par un complexe majeur d'histocompatibilité

  2013cites this paper
• Molecular description of how MART-1 specific T-cell receptors recognize structurally diverse melanoma antigens

  2013cites this paper
• Quelques exemples de biologie structurale.Mécanismes de reconnaissance et de signalisation de l’hôte face aux pathogènes et au soi-altéré ; recherche de nouvelles molécules thérapeutiques

  2012cites this paper
• Structural and dynamic control of T‐cell receptor specificity, cross‐reactivity, and binding mechanism

  2012cites this paper
• Autologous HIV-1 Clade-B Nef Peptides Elicit Increased Frequency, Breadth and Function of CD8+ T-Cells Compared to Consensus Peptides

  2012influential citation
• Steric recognition of T‐cell receptor contact residues is required to map mutant epitopes by immunoinformatical programmes

  2012cites this paper
• Degenerate T-cell Recognition of Peptides on MHC Molecules Creates Large Holes in the T-cell Repertoire

  2012cites this paper
• Resistance-associated epitopes of HIV-1C—highly probable candidates for a multi-epitope vaccine

  2012cites this paper
• Lessons learned from HIV-1 vaccine trials: new priorities and directions

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

  2012cites this paper
• Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms

  2012influential citation
• Unexpected T‐cell recognition of an altered peptide ligand is driven by reversed thermodynamics

  2012cites this paper
• Cross-reactivity of T cells and its role in the immune system.

  2012cites this paper
• Structural basis for self‐recognition by autoimmune T‐cell receptors

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

  2012cites this paper
• The Antiviral Efficacy of HIV-Specific CD8+ T-Cells to a Conserved Epitope Is Heavily Dependent on the Infecting HIV-1 Isolate

  2011cites this paper
• Understanding TR Binding to pMHC Complexes: How Does a TR Scan Many pMHC Complexes yet Preferentially Bind to One

  2011cites this paper
• Immune Receptors

  2011cites this paper
• TCRs Used in Cancer Gene Therapy Cross-React with MART-1/Melan-A Tumor Antigens via Distinct Mechanisms

  2011cites this paper
• Antigens via Distinct Mechanisms Cross-React with MART-1/Melan-A Tumor TCRs Used in Cancer Gene Therapy

  2011cites this paper
• A Single Autoimmune T Cell Receptor Recognizes More Than a Million Different Peptides*

  2011cites this paper
• T-Cell Immune Responses Against Env from CRF12_BF and Subtype B HIV-1 Show High Clade-Specificity that Can Be Overridden by Multiclade Immunizations

  2011cites this paper
• Dimerization of Soluble Disulfide Trap Single-Chain Major Histocompatibility Complex Class I Molecules Dependent on Peptide Binding Affinity

  2011cites this paper
• Binding of Efb from Staphylococcus aureus to Fibrinogen Blocks Neutrophil Adherence*

  2011cites this paper
• Global trends in molecular epidemiology of HIV-1 during 2000–2007

  2011cites this paper
• Analysis of receptor-ligand interactions by surface plasmon resonance.

  2011cites this paper
• Molecular Basis for LLT1 Protein Recognition by Human CD161 Protein (NKRP1A/KLRB1)

  2011cites this paper
• Antigen Potency and Maximal Efficacy Reveal a Mechanism of Efficient T Cell Activation

  2011cites this paper
• Expression and Purification of Isotopically Enriched MHC Binding Immunogenic Peptides for NMR Studies

  2011influential citation