Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis

Jessica Bruder, Katherina Siewert, Birgit Obermeier, Joachim Malotka, Peter Scheinert, Josef Kellermann, Takuya Ueda, Reinhard Hohlfeld, Klaus Dornmair

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)20986-20995
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number25
DOIs
Publication statusPublished - 2012 Jun 15
Externally publishedYes

Fingerprint

Myositis
T-cells
T-Cell Antigen Receptor
T-Lymphocytes
Antigens
Amino Acyl-tRNA Synthetases
Mutagenesis
Autoantibodies
Muscle
Epitopes
Histidine-tRNA Ligase
Inclusion Body Myositis
Tissue
Complementarity Determining Regions
Polymyositis
Muscles
Peptide Initiation Factors
Proteins
Fibers
Post Translational Protein Processing

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Bruder, J., Siewert, K., Obermeier, B., Malotka, J., Scheinert, P., Kellermann, J., ... Dornmair, K. (2012). Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis. Journal of Biological Chemistry, 287(25), 20986-20995. https://doi.org/10.1074/jbc.M112.356709

Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis. / Bruder, Jessica; Siewert, Katherina; Obermeier, Birgit; Malotka, Joachim; Scheinert, Peter; Kellermann, Josef; Ueda, Takuya; Hohlfeld, Reinhard; Dornmair, Klaus.

In: Journal of Biological Chemistry, Vol. 287, No. 25, 15.06.2012, p. 20986-20995.

Research output: Contribution to journalArticle

Bruder, J, Siewert, K, Obermeier, B, Malotka, J, Scheinert, P, Kellermann, J, Ueda, T, Hohlfeld, R & Dornmair, K 2012, 'Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis', Journal of Biological Chemistry, vol. 287, no. 25, pp. 20986-20995. https://doi.org/10.1074/jbc.M112.356709
Bruder J, Siewert K, Obermeier B, Malotka J, Scheinert P, Kellermann J et al. Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis. Journal of Biological Chemistry. 2012 Jun 15;287(25):20986-20995. https://doi.org/10.1074/jbc.M112.356709
Bruder, Jessica ; Siewert, Katherina ; Obermeier, Birgit ; Malotka, Joachim ; Scheinert, Peter ; Kellermann, Josef ; Ueda, Takuya ; Hohlfeld, Reinhard ; Dornmair, Klaus. / Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 25. pp. 20986-20995.
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