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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. The Journal of Biological Chemistry, 287(25), 20986-20995. doi:10.1074/jbc.M112.356709.

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 Creators:
Bruder, Jessica1, Author           
Siewert, Katherina1, Author           
Obermeier, Birgit1, Author           
Malotka, Joachim1, Author           
Scheinert, Peter, Author
Kellermann, Josef, Author
Ueda, Takuya, Author
Hohlfeld, Reinhard1, Author           
Dornmair, Klaus1, Author           
Affiliations:
1Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society, ou_1113547              

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Free keywords: TRANSFER-RNA SYNTHETASE; ANTIGEN RECOGNITION; POLYMYOSITIS; MHC; MUSCLE; LYMPHOCYTES; REPERTOIRE; BINDING; DERMATOMYOSITIS; AUTOANTIGENS
 Abstract: 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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Language(s): eng - English
 Dates: 2012-06-15
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000306416800020
DOI: 10.1074/jbc.M112.356709
 Degree: -

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Title: The Journal of Biological Chemistry
  Other : JBC
  Abbreviation : J. Biol. Chem.
Source Genre: Journal
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Publ. Info: Baltimore, etc. : American Society for Biochemistry and Molecular Biology [etc.]
Pages: - Volume / Issue: 287 (25) Sequence Number: - Start / End Page: 20986 - 20995 Identifier: ISSN: 0021-9258
CoNE: https://pure.mpg.de/cone/journals/resource/954925410826_1