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

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons61200

Bruder,  Jessica
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons39075

Siewert,  Katherina
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons39013

Obermeier,  Birgit
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons38981

Malotka,  Joachim
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons38897

Hohlfeld,  Reinhard
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons38805

Dornmair,  Klaus
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

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Zitation

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.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-000F-E5AA-A
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.