title: A structural basis for CD8+ T cell-dependent recognition of non-homologous peptide ligands: implications for molecular mimicry in autoreactivity.
abstract: Molecular mimicry of self-epitopes by viral antigens is one possible pathogenic mechanism underlying induction of autoimmunity. A self-epitope, mDBM, derived from mouse dopamine beta-mono-oxygenase (KALYDYAPI) sharing 44% sequence identity with the lymphocytic choriomeningitis virus-derived immunodominant epitope gp33 (KAVYNFATC/M), has previously been identified as a cross-reactive self-ligand, presentation of which results in autoimmunity. A rat peptide homologue, rDBM (KALYNYAPI, 56% identity to gp33), which displayed similar properties to mDBM, has also been identified. We herein report the crystal structure of H-2Db.rDBM and a comparison with the crystal structures of the cross-reactive H-2Db.gp33 and non-cross-reactive H-2Db.gp33 (V3L) escape variant (KALYNFATM, 88% identity to gp33). Despite the large sequence disparity, rDBM and gp33 peptides are presented in nearly identical manners by H-2Db, with a striking juxtaposition of the central sections of both peptides from residues p3 to p7. The structural similarity provides H-2Db in complex with either a virus-derived or a dopamine beta-mono-oxygenase-derived peptide with a shared antigenic identity that conserves the positioning of the heavy chain and peptide residues that interact with the T cell receptor (TCR). This stands in contrast to the structure of H-2Db.gp33 (V3L), in which a single conserved mutation, also present in rDBM, induces large movements of both the peptide backbone and the side chains that interact with the TCR. The TCR-interacting surfaces of the H-2Db.rDBM and H-2Db.gp33 major histocompatibility complexes are very similar with regard to shape, topology, and charge distribution, providing a structural basis for CD8 T cell activation by molecular mimicry and potential subsequent development of autoreactivity.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Microbiology and Tumor Biology Center, and Strategic Research Center IRIS for Studies of Integrated Recognition in the Immune System, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Sandalova
authors.forename: Jakob
authors.initials: J
authors.lastname: Michaëlsson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Jacob
authors.initials: J
authors.lastname: Odeberg
authors.forename: Gunter
authors.initials: G
authors.lastname: Schneider
authors.forename: Klas
authors.initials: K
authors.lastname: Kärre
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D018360:Crystallography, X-Ray; D004299:Dopamine beta-Hydroxylase / Q000737:chemistry / Q000276:immunology; D000939:Epitopes / Q000737:chemistry; D006023:Glycoproteins / Q000276:immunology; D006183:H-2 Antigens / Q000737:chemistry* / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D008024:Ligands; D051379:Mice; D018716:Molecular Mimicry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D000939:Epitopes; D006023:Glycoproteins; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D008024:Ligands; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; D004299:Dopamine beta-Hydroxylase