Crystal Structure of the β Chain of a T Cell Antigen Receptor

Bentley, G.A.; Boulot, G.; Karjalainen, Klaus; Mariuzza, Roy A.

doi:10.1126/science.7701320

Cited by 259 publications

(169 citation statements)

References 36 publications

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“…Our data support the assumption that the structure of the TcR resembles that of an immunoglobulin Fab fragment (15)(16)(17). Thus, the TcR would engage a surface area of '800 A2, much like the size and shape the Ha255-262-Kk complex as it is outlined in Fig.…”

supporting

confidence: 75%

“…9). The specificity of peptide-MHC interactions has been described in great detail, whereas little biochemical (10)(11)(12)(13)(14) or structural (15,16) data exist on T-cell recognition. It is generally assumed that self-MHC accounts for the majority of the T-cell target structure, whereas antigenic peptides constitute a smaller, albeit highly heterogeneous portion of this structure (8,17).…”

mentioning

confidence: 99%

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Shared fine specificity between T-cell receptors and an antibody recognizing a peptide/major histocompatibility class I complex.

Stryhn

Andersen

Pedersen

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Cytotoxic T cells recognize mosaic structures consisting of target peptides embedded within self-major histocompatibility complex (MH) class I molecules. This structure has been described in great detail for several peptide-MHC complexes. In contrast, how T-cell receptors recognize peptide-MHC complexes have been less well characterized. We have used a complete set of singly substituted analogs of a mouse MHC class I, Kk-restricted peptide, influenza hemagglutinin (Ha)25s.262, to address the binding specificity of this MHC molecule. Using the same peptide-MHC complexes we determined the fine specificity of two Ha255.262-specific, Kk-restricted T cells, and of a unique antibody, pSAN, specific for the same peptide-MHC complex.Independently, a model of the Ha25sz262-Kk complex was generated through homology modeling and molecular mechanics refinement. The functional data and the model corroborated each other showing that peptide residues 1, 3, 4, 6, and 7 were exposed on the MHC surface and recognized by the T cells. Thus, the majority, and perhaps all, of the side chains of the non-primary anchor residues may be available for T-cell recognition, and contribute to the stringent specificity of T cells. A striking similarity between the specificity of the T cells and that of the pSAN antibody was found and most of the peptide residues, which could be recognized by the T cells, could also be recognized by the antibody.Eradicating infected cells is an important strategy in the defense against intracellular pathogens. One of the cell types involved, the CD8+ cytotoxic T cells (CTLs), has developed a unique and quite elaborate mode of recognition: only antigens, which are presented in association with class

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supporting

confidence: 75%

mentioning

confidence: 99%

Shared fine specificity between T-cell receptors and an antibody recognizing a peptide/major histocompatibility class I complex.

Stryhn

Andersen

Pedersen

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…The association of TCRs at the cell surface with the accessory molecules CD4 or CD8 also may influence the functional affinity of TCRs (3). Despite these differences, the three-dimensional structures of the two proteins are remarkably similar, with the hypervariable regions forming loops on a single face of the molecule that contacts the antigen (4)(5)(6)(7).…”

mentioning

confidence: 91%

Selection of functional T cell receptor mutants from a yeast surface-display library

Kieke

Shusta

Boder

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

161

128

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The heterodimeric ␣␤ T cell receptor (TCR) for antigen is the key determinant of T cell specificity. The structure of the TCR is very similar to that of antibodies, but the engineering of TCRs by directed evolution with combinatorial display libraries has not been accomplished to date. Here, we report that yeast surface display of a TCR was achieved only after the mutation of specific variable region residues. These residues are located in two regions of the TCR, at the interface of the ␣-and ␤-chains and in the ␤-chain framework region that is thought to be in proximity to the CD3 signal-transduction complex. The mutations are encoded naturally in many antibody variable regions, indicating specific functional differences that have not been appreciated between TCRs and antibodies. The identification of these residues provides an explanation for the inherent difficulties in the display of wild-type TCRs compared with antibodies. Yeastdisplayed mutant TCRs bind specifically to the peptide͞MHC antigen, enabling engineering of soluble T cell receptors as specific T cell antagonists. This strategy of random mutagenesis followed by selection for surface expression may be of general use in the directed evolution of other eukaryotic proteins that are refractory to display.T cell receptors (TCRs) and antibodies have evolved to recognize different classes of ligands. Antibodies function as membrane-bound and soluble proteins that bind to soluble antigens, whereas TCRs function only as membrane-bound molecules that bind to cell-associated peptide͞MHC antigens. All of the energy of the antibody:antigen interaction focuses on the foreign antigen, whereas a substantial fraction of the energy of the TCR:peptide͞MHC interaction seems to be directed at the self-MHC molecule (1). In addition, antibodies can have ligand-binding affinities that are orders of magnitude higher than those of TCRs, largely because of the processes of somatic mutation and affinity maturation. In their normal cellular context, TCRs do not undergo somatic mutation and the processes of thymic selection seem to operate by maintaining a narrow window of affinities (2). The association of TCRs at the cell surface with the accessory molecules CD4 or CD8 also may influence the functional affinity of TCRs (3). Despite these differences, the three-dimensional structures of the two proteins are remarkably similar, with the hypervariable regions forming loops on a single face of the molecule that contacts the antigen (4-7).Based on their structural similarities, it is somewhat surprising that there have been significant differences in the success of producing soluble and surface-displayed forms of the extracellular domains of TCRs and antibodies in heterologous expression systems. Many antibodies have now been expressed at high yield and solubility as either intact or Fab-fragment forms or as single-chain (sc) fragment-variable (Fv) proteins. In addition, there are numerous antigen-binding Fv fragments that have been isolated de novo and͞or improved through...

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“…Conversely, crystallographical studies on a BV8S2A1 encoded TCR ␤ chain and an AV4S2 TCR ␣ chain fragment confirmed that TCR are folded in an Ig-like manner but also indicated significant structural differences, such as different hinge structures and interstrand hydrogen bond formation (4,5). Little is still known on how TCR bind their ligand (MHCpeptide complexes).…”

Section: From the ‡Ludwig Institute For Cancer Research Lausanne Bramentioning

confidence: 99%

Differential Roles of T Cell Receptor α and β Chains in Ligand Binding Among H-2Kd-restricted Cytolytic T Lymphocyte Clones Specific for a Photoreactive Plasmodium berghei Circumsporozoite Peptide Derivative

Anjuère

Kuznetsov

Romero

et al. 1997

Journal of Biological Chemistry

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To study the interaction of T cell receptor with its ligand, a complex of a major histocompatibility complex molecule and a peptide, we derived H-2K d -restricted cytolytic T lymphocyte clones from mice immunized with a Plasmodium berghei circumsporozoite peptide (PbCS) 252-260 (SYIPSAEKI) derivative containing photoreactive N ⑀ -[4-azidobenzoyl] lysine in place of Pro-255. This residue and Lys-259 were essential parts of the epitope recognized by these clones. Most of the clones expressed BV1S1A1 encoded ␤ chains along with specific complementary determining region (CDR) 3␤ regions but diverse ␣ chain sequences. Surprisingly, all T cell receptors were preferentially photoaffinity labeled on the ␣ chain. For a representative T cell receptor, the photoaffinity labeled site was located in the V␣ C-strand. Computer modeling suggested the presence of a hydrophobic pocket, which is formed by parts of the V␣/J␣ C-, F-, and G-strands and adjacent CDR3␣ residues and structured to be able to avidly bind the photoreactive ligand side chain. We previously found that a T cell receptor specific for a PbCS peptide derivative containing this photoreactive side chain in position 259 similarly used a hydrophobic pocket located between the junctional CDR3 loops. We propose that this nonpolar domain in these locations allow T cell receptors to avidly and specifically bind epitopes containing non-peptidic side chains.

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Crystal Structure of the β Chain of a T Cell Antigen Receptor

Cited by 259 publications

References 36 publications

Shared fine specificity between T-cell receptors and an antibody recognizing a peptide/major histocompatibility class I complex.

Shared fine specificity between T-cell receptors and an antibody recognizing a peptide/major histocompatibility class I complex.

Selection of functional T cell receptor mutants from a yeast surface-display library

Differential Roles of T Cell Receptor α and β Chains in Ligand Binding Among H-2Kd-restricted Cytolytic T Lymphocyte Clones Specific for a Photoreactive Plasmodium berghei Circumsporozoite Peptide Derivative

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