ACCELERATION OF SPONTANEOUS DIABETES IN TCR-BETA-TRANSGENIC NONOBESE DIABETIC MICE BY BETA-CELL CYTOTOXIC CD8(-CELLS EXPRESSING IDENTICAL ENDOGENOUS TCR-ALPHA CHAINS() T)

The role of target cell autoantigens and their repertoire vs those of foreign Ags, superantigens, or non-Ag-specific stimuli in the activati on and recruitment, of effector T cells in most spontaneous models of autoimmune diseases remains elusive, Here we report on the use of sing le TCR-beta transgenic mice to study the mechanisms that drive the acc umulation of pathogenic T cells in the pancreatic islets of nonobese d iabetic (NOD) mice, a model for insulin-dependent diabetes mellitus, E xpression of the V beta 8.1(+) TCR-beta rearrangement of a diabetogeni c H-2K(d)-restricted beta cell cytotoxic CD8(+) T fell (beta-CTL) clon e in NOD mice caused a 10-fold increase ill the peripheral precursor f requency of beta-CTL and a selective acceleration of the recruitment o f CD8(+) T cells to the pancreatic islets of prediabetic animals. This resulted in an earlier onset and a faster progression of beta cell de pletion, and fed to a dramatic acceleration of the onset of diabetes. Most islet-derived beta-CTL from diabetic transgenic NOD mice expresse d an endogenously-derived TCR-alpha sequence identical to that of the clonotype donating the TCR-beta transgene, and a TCR-alpha-CDR3 sequen ce homologous to those expressed by most islet-derived beta-CTL from n ontransgenic NBD mice, TCR-beta transgene expression did not change th e peripheral frequency of beta cell-specific CD4(+) T cells, the rate at which these cells accumulated in the pancreatic islets, or the inci dence of diabetes. Taken together, our data indicate that retention of CD8(+) and CD4(+) T cells in the pancreatic islets of NOD mice is dri ven by beta cell autoantigens, rather than by local superantigens or n on-Ag-specific stimuli, and that beta-CTL are major effectors of beta cell damage in spontaneous insulin-dependent diabetes mellitus.