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Chapter 14 : Structural Basis of T-Cell Receptor Specificity and Cross-Reactivity: Implications for Pathogenesis of Human Autoimmune Diseases

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Abstract:

Activation of autoreactive T cells is critical for the induction of autoimmunity. Several mechanisms may be responsible for the activation of autoreactive T cells in autoimmune diseases. These include cross-reactive microbial peptides (molecular mimicry), viral or bacterial superantigens, release of autoantigen during inflammation, or bystander activation. The molecular mimicry hypothesis postulates that there is significant cross-reactivity between viral and bacterial T-cell epitopes and human self-peptides and that such cross-reactivity can initiate an autoimmune process. At first sight T-cell receptor (TCR) recognition appears to be exquisitely specific since even minor substitutions in a T-cell epitope can diminish or abrogate T-cell activation. The structure of HLA-DR2 with the bound myelin basic protein (MBP) peptide (residues 85 to 99) was determined by X-ray crystallography as a step toward defining molecular mimicry at a structural level. For this purpose, HLA-DR2 was expressed as a soluble protein in the baculovirus system. In the crystal structures of MHC class I-peptide complexes, the P5 side chain occupies a central pocket created by the CDR3 loops of α β TCRs. The dEV8 self-peptide represents a ligand with a low affinity for the 2C TCR. The diverse nature of the molecular mimicry peptides and the ubiquitous presence of some of these pathogens may make it difficult to establish a direct epidemiological link between infectious agents and the occurrence of certain autoimmune diseases.

Citation: Appel H, Wucherpfennig K. 2000. Structural Basis of T-Cell Receptor Specificity and Cross-Reactivity: Implications for Pathogenesis of Human Autoimmune Diseases, p 197-213. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch14

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Figures

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Figure 1

Crystal structure of the complex of HLA-DR2 and the MBP peptide (residues 85 to 99). (For color version of figure, see Color Plates, p. 277.) (A) Overview of the structure. MBP peptide residues V89, F92,195, and T97 occupy the P1, P4, P6, and P9 pockets of the HLA-DR2 binding site, respectively. (B) Solvent-exposed residues that are important for TCR recognition of the MBP peptide (residues 85 to 99). MBP residues H90, F91, and K93 were identified as important TCR contact residues. These are located at the P2, P3, and P5 positions, respectively, and are available for interaction with the TCR. (C) P4 pocket of the HLA-DR2 binding site. This pocket is occupied by F92 of the MBP peptide. The necessary room for this aromatic side chain is created by the DRβ71 polymorphism. (D) Close-up view of MBP peptide residues that are important for TCR recognition. Preferences at positions P-1, P2, P3, and P5 were considered in the search criteria for cross-reactive microbial peptides. Reprinted from ( ) with permission of the publisher.

Citation: Appel H, Wucherpfennig K. 2000. Structural Basis of T-Cell Receptor Specificity and Cross-Reactivity: Implications for Pathogenesis of Human Autoimmune Diseases, p 197-213. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch14
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Image of Figure 2
Figure 2

Electron density and model of the MBP peptide in the binding site of HLA-DR2. (For color version of figure, see Color Plates, p. 278.) (A) Electron density of the MBP peptide bound to HLA-DR2. The C terminus of the peptide (P10, P11) is partially disordered. (B) Superposition of the two MBP peptides in the asymmetric unit. The DR2-MBP peptide complex crystallized as a dimer of dimers, like other HLA-DR molecules ( ). The model for the MBP peptide includes residues P-3 to P11 and P-4 to P10 for the two copies in the asymmetric unit, yellow and blue, respectively. The peptide backbones superimpose in the P-l to P4 segment and are more divergent in the C-terminal segment due to different crystal contacts. A crystal contact between peptide residue P-3 in one molecule and P5 from a symmetrically related molecule stabilizes the N terminus of one peptide, enabling P-4 to be included in the model for this peptide and P5 Lys to be included in the model for the other peptide. Reprinted from ( ) with permission of the publisher.

Citation: Appel H, Wucherpfennig K. 2000. Structural Basis of T-Cell Receptor Specificity and Cross-Reactivity: Implications for Pathogenesis of Human Autoimmune Diseases, p 197-213. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch14
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Tables

Generic image for table
Table 1

Requirements for development of an autoimmune disease following an initial activation of autoreactive T cells

Citation: Appel H, Wucherpfennig K. 2000. Structural Basis of T-Cell Receptor Specificity and Cross-Reactivity: Implications for Pathogenesis of Human Autoimmune Diseases, p 197-213. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch14
Generic image for table
Table 2

Sequences of microbial peptides that activate human MBP-specific T-cell clones

Citation: Appel H, Wucherpfennig K. 2000. Structural Basis of T-Cell Receptor Specificity and Cross-Reactivity: Implications for Pathogenesis of Human Autoimmune Diseases, p 197-213. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch14
Generic image for table
Table 3

Alignment of microbial peptides based on crystal structure of HLA-DR2-MBP peptide complex

Citation: Appel H, Wucherpfennig K. 2000. Structural Basis of T-Cell Receptor Specificity and Cross-Reactivity: Implications for Pathogenesis of Human Autoimmune Diseases, p 197-213. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch14

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