Autoantigen-Induced Focusing of V beta 13(+) T Cells Precedes Onset of Autoimmune Diabetes in the LEW.1WR1 Rat

作者：Eberwine Ryan A; Cort Laura; Habib Michael; Mordes John P; Blankenhorn Elizabeth P^*

来源：Diabetes, 2014, 63(2): 596-604.

DOI：10.2337/db13-0462

The earliest events leading to autoimmune type 1 diabetes (T1D) are not known in any species. A T-cell receptor (TCR)-variable region, TCR-V13, is required for susceptibility to autoimmune diabetes in rats, and selective depletion of V13(+) T cells with an allele-specific monoclonal antibody prevents disease in multiple rat strains. To investigate the role of V13 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. V13(+) 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). V13(+) transcripts increased in LEW.1WR1 islets during diabetes progression, but not in resistant rats. We also analyzed transcript clonality of rat TCR-V5, 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 V5(+) transcripts in prediabetic LEW.1WR1 islets, suggesting that rat V5 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.

• 出版日期2014-2