title: Crossreactivity of a human autoimmune TCR is dominated by a single TCR loop.
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.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Dhruv K
authors.initials: DK
authors.lastname: Sethi
authors.forename: Susana
authors.initials: S
authors.lastname: Gordo
authors.forename: David A
authors.initials: DA
authors.lastname: Schubert
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfennig
mesh_terms: D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry* / Q000276:immunology; D015551:Autoimmunity; D001426:Bacterial Proteins / Q000737:chemistry* / Q000276:immunology; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000276:immunology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D018139:Simplexvirus / Q000737:chemistry; D014764:Viral Proteins / Q000737:chemistry* / Q000276:immunology
chemical_list: D001324:Autoantigens; D001426:Bacterial Proteins; D004676:Myelin Basic Protein; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins