MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I-RESTRICTED T-CELLS ARE REQUIRED FOR ALL BUT THE END STAGES OF DIABETES DEVELOPMENT IN NONOBESE DIABETIC MICE AND USE A PREVALENT T-CELL RECEPTOR-ALPHA CHAIN GENE REARRANGEMENT

Nonobese diabetic (NOD) mice develop insulin-dependent diabetes mellit us due to autoimmune T lymphocyte-mediated destruction of pancreatic b eta cells. Although both major histocompatibility complex class I-rest ricted CD8(+) and class II-restricted CD4(+) T cell subsets are requir ed, the specific role each subset plays in the pathogenic process is s till unclear. Here we show that class I-dependent T cells are required for all but the terminal stages of autoimmune diabetes development. T o characterize the diabetogenic CD8(+) T cells responsible, we isolate d and propagated in vitro CD8(+) T cells from the earliest insulitic l esions of NOD mice, They were cytotoxic to NOD islet cells, restricted to H-2K(d), and showed a diverse T cell receptor beta chain repertoir e. In contrast, their alpha chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity determin ing region 3 loop and a prevalence of V alpha 17 family members freque ntly joined to the J alpha 42 gene segment. These results suggest that a number of the CD8(+) T cells participating in the initial phase of autoimmune beta cell destruction recognize a common structural compone nt of K-d/peptide complexes on pancreatic beta cells, possibly a singl e peptide.