Target specificity of an autoreactive pathogenic human ??-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 ??-T cell receptor (??-TCR) for antigen. In a rare variant of myositis, muscle fibers are similarly attacked by CD8-negative T cells expressing the ??-TCR (??-T cell-mediated myositis). We investigated the antigen specificity of a human ??-TCR previously identified in an autoimmune tissue lesion of ??-T cell-mediated myositis. We show that this V?1.3V?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 ?-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 ??-TCR chains contribute to antigen recognition. M88 is the only known example of a molecularly characterized ??-TCR expressed by autoaggressive T cells in tissue. The observation that AA-RS are targeted by a ??-T cell and by autoantibodies reveals an unexpected link between T cell and antibody responses in autoimmune myositis.

SUBMITTER: Bruder J 

PROVIDER: S-EPMC3375522 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature