Abstract
Self-reactive CD4 T cells are thought to have a central role in the pathogenesis of many chronic inflammatory human diseases. Microbial peptides can activate self-reactive T cells, but the structural basis for such crossreactivity is not well understood. The Hy.1B11 T cell receptor (TCR) originates from a patient with multiple sclerosis and recognizes the self-antigen myelin basic protein. Here we report the structural mechanism of TCR crossreactivity with two distinct peptides from human pathogens. The structures show that a single TCR residue (CDR3α F95) makes the majority of contacts with the self-peptide and both microbial peptides (66.7-80.6%) due to a highly tilted TCR-binding topology on the peptide-MHC surface. Further, a neighbouring residue located on the same TCR loop (CDR3α E98) forms an energetically critical interaction with the MHC molecule. These data show how binding by a self-reactive TCR favors crossreactivity between self and microbial antigens.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Autoantigens / chemistry*
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Autoantigens / immunology
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Autoimmunity
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Bacterial Proteins / chemistry*
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Bacterial Proteins / immunology
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Binding Sites
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CD4-Positive T-Lymphocytes / chemistry
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / pathology
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Cross Reactions
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Crystallography, X-Ray
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Humans
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Models, Molecular
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Molecular Sequence Data
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Multiple Sclerosis / metabolism
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Multiple Sclerosis / pathology
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Myelin Basic Protein / chemistry*
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Myelin Basic Protein / immunology
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Protein Binding
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Pseudomonas aeruginosa / chemistry
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Receptors, Antigen, T-Cell / chemistry*
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Receptors, Antigen, T-Cell / immunology
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Sequence Alignment
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Sequence Homology, Amino Acid
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Simplexvirus / chemistry
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Viral Proteins / chemistry*
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Viral Proteins / immunology
Substances
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Autoantigens
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Bacterial Proteins
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Myelin Basic Protein
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Receptors, Antigen, T-Cell
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Viral Proteins