title: Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis.
abstract: In polymyositis and inclusion body myositis, muscle fibers are surrounded and invaded by CD8-positive cytotoxic T cells expressing the αβ-T cell receptor (αβ-TCR) for antigen. In a rare variant of myositis, muscle fibers are similarly attacked by CD8-negative T cells expressing the γδ-TCR (γδ-T cell-mediated myositis). We investigated the antigen specificity of a human γδ-TCR previously identified in an autoimmune tissue lesion of γδ-T cell-mediated myositis. We show that this Vγ1.3Vδ2-TCR, termed M88, recognizes various proteins from different species. Several of these proteins belong to the translational apparatus, including some bacterial and human aminoacyl-tRNA synthetases (AA-RS). Specifically, M88 recognizes histidyl-tRNA synthetase, an antigen known to be also targeted by autoantibodies called anti-Jo-1. The M88 target epitope is strictly conformational, independent of post-translational modification, and exposed on the surface of the respective antigenic protein. Extensive mutagenesis of the translation initiation factor-1 from Escherichia coli (EcIF1), which served as a paradigm antigen with known structure, showed that a short α-helical loop around amino acids 39 to 42 of EcIF1 is a major part of the M88 epitope. Mutagenesis of M88 showed that the complementarity determining regions 3 of both γδ-TCR chains contribute to antigen recognition. M88 is the only known example of a molecularly characterized γδ-TCR expressed by autoaggressive T cells in tissue. The observation that AA-RS are targeted by a γδ-T cell and by autoantibodies reveals an unexpected link between T cell and antibody responses in autoimmune myositis.
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilians University, D-81377 Munich, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bruder
authors.forename: Katherina
authors.initials: K
authors.lastname: Siewert
authors.forename: Birgit
authors.initials: B
authors.lastname: Obermeier
authors.forename: Joachim
authors.initials: J
authors.lastname: Malotka
authors.forename: Peter
authors.initials: P
authors.lastname: Scheinert
authors.forename: Josef
authors.initials: J
authors.lastname: Kellermann
authors.forename: Takuya
authors.initials: T
authors.lastname: Ueda
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.forename: Klaus
authors.initials: K
authors.lastname: Dornmair
mesh_terms: D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology; D006643:Histidine-tRNA Ligase / Q000235:genetics / Q000276:immunology; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics / Q000276:immunology*; D016296:Mutagenesis; D017285:Polymyositis / Q000235:genetics / Q000276:immunology*; D017433:Protein Structure, Secondary; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D029968:Escherichia coli Proteins; D009124:Muscle Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D006643:Histidine-tRNA Ligase