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  Target Specificity of an Autoreactive Pathogenic Human gamma delta-T Cell Receptor in Myositis

Bruder, J., Siewert, K., Obermeier, B., Malotka, J., Scheinert, P., Kellermann, J., et al. (2012). Target Specificity of an Autoreactive Pathogenic Human gamma delta-T Cell Receptor in Myositis. JOURNAL OF BIOLOGICAL CHEMISTRY, 287(25), 20986-20995. doi:10.1074/jbc.M112.356709.

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Bruder, Jessica1, Autor           
Siewert, Katherina1, Autor           
Obermeier, Birgit1, Autor           
Malotka, Joachim1, Autor           
Scheinert, Peter2, Autor
Kellermann, Josef2, Autor
Ueda, Takuya2, Autor
Hohlfeld, Reinhard1, Autor           
Dornmair, Klaus1, Autor           
Affiliations:
1Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society, ou_1113547              
2External Organizations, ou_persistent22              

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Schlagwörter: TRANSFER-RNA SYNTHETASE; ANTIGEN RECOGNITION; POLYMYOSITIS; MHC; MUSCLE; LYMPHOCYTES; REPERTOIRE; BINDING; DERMATOMYOSITIS; AUTOANTIGENS
 Zusammenfassung: In polymyositis and inclusion body myositis, muscle fibers are surrounded and invaded by CD8-positive cytotoxic T cells expressing the alpha beta-T cell receptor (alpha beta-TCR) for antigen. In a rare variant of myositis, muscle fibers are similarly attacked by CD8-negative T cells expressing the gamma delta-TCR (gamma delta-T cell-mediated myositis). We investigated the antigen specificity of a human gamma delta-TCR previously identified in an autoimmune tissue lesion of gamma delta-T cell-mediated myositis. We show that this V gamma 1.3V delta 2-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 alpha-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 gamma delta-TCR chains contribute to antigen recognition. M88 is the only known example of a molecularly characterized gamma delta-TCR expressed by autoaggressive T cells in tissue. The observation that AA-RS are targeted by a gamma delta-T cell and by autoantibodies reveals an unexpected link between T cell and antibody responses in autoimmune myositis.

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Sprache(n): eng - English
 Datum: 2012-06-15
 Publikationsstatus: Erschienen
 Seiten: 10
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: ISI: 000306416800020
DOI: 10.1074/jbc.M112.356709
 Art des Abschluß: -

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Titel: JOURNAL OF BIOLOGICAL CHEMISTRY
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Seiten: - Band / Heft: 287 (25) Artikelnummer: - Start- / Endseite: 20986 - 20995 Identifikator: ISSN: 0021-9258