Autoantigen-induced focusing of V?13+ T cells precedes onset of autoimmune diabetes in the LEW.1WR1 rat.

ABSTRACT: The earliest events leading to autoimmune type 1 diabetes (T1D) are not known in any species. A T-cell receptor (TCR)-variable region, TCR-V?13, is required for susceptibility to autoimmune diabetes in rats, and selective depletion of V?13(+) T cells with an allele-specific monoclonal antibody prevents disease in multiple rat strains. To investigate the role of V?13 early in diabetes, we examined islet T-cell transcripts in susceptible (LEW.1WR1) and resistant (LEW.1W and Wistar Furth) strains induced with polyinosinic:polycytidylic acid. V?13(+) T cells displayed antigenic focusing in LEW.1WR1 islets 5 days postinduction and were characterized by a substantial decrease in complementarity determining region 3 diversity. This occurred prior to significant islet T-cell accumulation (day 7) or frank diabetes (days 10-14). V?13(+) transcripts increased in LEW.1WR1 islets during diabetes progression, but not in resistant rats. We also analyzed transcript clonality of rat TCR-V?5, an ortholog of the dominant TCR-V? chain found on insulin B:9-23-reactive T cells in nonobese diabetic rat islets. We observed clonal expansion of V?5(+) transcripts in prediabetic LEW.1WR1 islets, suggesting that rat V?5 is also an important component of islet autoantigen recognition. These data provide additional evidence that genome-encoded TCR sequences are important determinants of genetic susceptibility to T1D.

SUBMITTER: Eberwine RA 

PROVIDER: S-EPMC3900547 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature