Crystal structure of a T cell receptor bound to an allogeneic MHC molecule

Reiser, Jean‐Baptiste; Darnault, Claudine; Guimezanes, Annick; Grégoire, Claude; Mosser, Thomas; Schmitt-Verhulst, Anne-Marie; Fontecilla‐Camps, Juan C.; Malissen, Bernard; Housset, D.; Mazza, Gilbert

doi:10.1038/79728

Cited by 200 publications

(161 citation statements)

References 37 publications

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“…Although alloreactive T cells can recognize structural determinants of the foreign MHC molecules independent of the bound peptides (5)(6)(7), it has become clear that, for most alloreactive T cells, recognition depends on peptides within the allo-MHC groove (5,6,8,9). Structural studies on alloreactive TCR complexed with allogeneic MHC molecules have confirmed the role played by peptides in alloreactivity (10,11). As originally proposed by Matzinger and Bevan (12), it thus appears that alloreactive TCRs exploit the similarities, rather than the differences, between the top of the helices of self-and allo-MHC molecules.…”

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confidence: 92%

EBV-Specific CD4+ T Cell Clones Exhibit Vigorous Allogeneic Responses

Landais

Morice

Long

et al. 2006

The Journal of Immunology

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Alloreactive T cells play a key role in mediating graft-vs-host disease and allograft rejection, and recent data suggest that most T cell alloreactivity resides within the CD4 T cell subset. Particularly, T cell responses to herpesvirus can shape the alloreactive repertoire and influence transplantation outcomes. In this study, we describe six distinct EBV-specific CD4+ T cell clones that cross-reacted with EBV-transformed lymphoblastoid cell lines (LCLs), dendritic cells, and endothelial cells expressing MHC class II alleles commonly found in the population. Allorecognition showed exquisite MHC specificity. These CD4+ T cell clones efficiently killed dendritic cells or LCLs expressing the cross-reactive allogeneic MHC class II molecules, whereas they did not kill autologous LCLs. Endothelial cells expressing the proper allogeneic MHC molecules were poorly killed, but they induced high-level TNF-α production by the EBV-specific CD4+ T cell clones. As already proposed, the strong alloreactivity toward LCLs suggest that these cells could be used for selective depletion of alloreactive T cells.

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mentioning

confidence: 92%

EBV-Specific CD4+ T Cell Clones Exhibit Vigorous Allogeneic Responses

Landais

Morice

Long

et al. 2006

The Journal of Immunology

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“…On the molecular level, the corollary of this hypothesis is that a TCR clonotype will exhibit sufficient intrinsic conformational diversity to crossreact with several molecular mimics and less structurally related pMHCI complexes (51)(52)(53). Although alloreactive and/or xenoreactive ligands have been identified for other TCRs (51,(53)(54)(55)(56), few cross-reactive syngeneic interactions between naturally occurring pMHCI and cognate TCR have been identified (57)(58)(59)(60). Indeed, to the best of our knowledge, this study is the first to characterize the interaction between a pathogen-reactive human TCR and a cross-reactive self-peptide in biophysical terms.…”

Section: Functional Optimization Of Soluble Tcrsmentioning

confidence: 99%

Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition

Laugel

Boulter

Lissin³

et al. 2005

Journal of Biological Chemistry

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The use of recombinant T cell receptors (TCRs) to target therapeutic interventions has been hindered by the naturally low affinity of TCR interactions with peptide major histocompatibility complex ligands. Here, we use multimeric forms of soluble heterodimeric ␣␤ TCRs for specific detection of target cells pulsed with cognate peptide, discrimination of quantitative changes in antigen display at the cell surface, identification of virusinfected cells, inhibition of antigen-specific cytotoxic T lymphocyte activation, and identification of cross-reactive peptides. Notably, the A6 TCR specific for the immunodominant HLA A2-restricted human T cell leukemia virus type 1 Tax 11-19 epitope bound to HLA A2-HuD 87-95 (K D 120 M by surface plasmon resonance), an epitope implicated as a causal antigen in the paraneoplastic neurological degenerative disorder anti-Hu syndrome. A mutant A6 TCR that exhibited dramatically increased affinity for cognate antigen (K D 2.5 nM) without enhanced cross-reactivity was generated; this TCR demonstrated potent biological activity even as a monomeric molecule. These data provide insights into TCR repertoire selection and delineate a framework for the selective modification of TCRs in vitro that could enable specific therapeutic intervention in vivo.Peptide major histocompatibility complex (pMHC) 1 antigens displayed on the surface of target cells are recognized by T cells via their specific T cell receptor (TCR) (1). The TCR coreceptors CD8 or CD4 bind to invariant domains of pMHC class I (pMHCI) or pMHC class II (pMHCII) and are known to facilitate the process of antigen recognition by T cells (2). Recent advances have enabled the generation of high quality soluble TCR, pMHCI, pMHCII, CD8, and CD4 proteins; these in turn have allowed the biophysical characterization of the interactions between these molecules. Accordingly, the TCR and CD4/8 co-receptors have been shown to have very low affinities (K D ϳ 10 Ϫ3 -10 Ϫ6 M) for cognate pMHC. Despite these low affinity interactions, however, the process of antigen engagement can initiate T cell recognition of antigen-presenting cells (APCs) bearing fewer than 10 copies of a specific pMHC complex (3, 4). The mechanisms by which these weak recognition events result in such exquisite sensitivity are not fully understood.The production of soluble recombinant ␣␤ T cell receptors has proved challenging. The main technical pitfall is heterodimeric instability in the absence of anchoring transmembrane domains and ␣/␤ pairing through an interchain disulfide bond. One of the commonest protein engineering strategies used in TCR studies to date has been the construction of singlechain TCRs. This technique, which takes advantage of the structural similarities between antibodies and TCRs, is based upon the single-chain Fv technology used to generate antibody fragments (5). In short, for the TCR it involves the cloning and expression of a unique chimerical open reading frame where the variable (V) ␣ and V␤ domains are paired with a protein linker (6, 7). Thes...

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“…However, at least some V-gene segments can use more than one set of interactions to bind a given MHC molecule. For example, two Vb2-containing TCRs with different peptide specificities show distinct docking footprints on the H-2K b a1 helix (Reiser et al 2000;Reiser et al 2003). The hypervariable CDR3 loops of the TCR and …”

Section: Structural Insights Into the Mechanism Of Mhc Restrictionmentioning

confidence: 99%

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Wucherpfennig¹,

Gagnon²,

Call³

et al. 2010

Cold Spring Harbor Perspectives in Biology

152

108

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The T-cell receptor (TCR)-CD3 complex serves as a central paradigm for general principles of receptor assembly, ligand recognition, and signaling in the immune system. There is no other receptor system that matches the diversity of both receptor and ligand components. The recent expansion of the immunological structural database is beginning to identify key principles of MHC and peptide recognition. The multicomponent assembly of the TCR complex illustrates general principles used by many receptors in the immune system, which rely on basic and acidic transmembrane residues to guide assembly. The intrinsic binding of the cytoplasmic domains of the CD31 and z chains to the inner leaflet of the plasma membrane represents a novel mechanism for control of receptor activation: Insertion of critical CD31 tyrosines into the hydrophobic membrane core prevents their phosphorylation before receptor engagement. LIGAND BINDING BY THE EXTRACELLULAR DOMAINS OF T-CELL RECEPTORS: STRUCTURAL BASIS OF ab AND gd TCR BINDING TO A DIVERSE GROUP OF LIGANDST he structures of many T-cellreceptors (TCRs) in their ligand-bound state have now been determined, allowing some of the general rules of antigen recognition to be distilled. Though the best studied interaction is the binding of abTCR with peptide-MHC complexes, it is highly instructive to compare the prototypical binding to peptide-MHC with the recognition of lipid antigen-CD1 complexes and engagement of nonclassical MHC class I molecules by gdTCRs. These comparisons show that the recognition strategies for these

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Crystal structure of a T cell receptor bound to an allogeneic MHC molecule

Cited by 200 publications

References 37 publications

EBV-Specific CD4+ T Cell Clones Exhibit Vigorous Allogeneic Responses

EBV-Specific CD4+ T Cell Clones Exhibit Vigorous Allogeneic Responses

Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

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