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 mellitus due to autoimmune T lymphocyte-mediated destruction of pancreatic [Beta] cells. Although both major histocompatibility complex class I-restricted [CD8.sup.+] and class II-restricted [CD4.sup.+] T cell subsets are required, the specific role each subset plays in the pathogenic process is still unclear. Here we show that class I-dependent T cells are required for all but the terminal stages of autoimmune diabetes development. To characterize the diabetogenic [CD8.sup.+] T cells responsible, we isolated and propagated in vitro [CD8.sup.+] T cells from the earliest insulitic lesions of NOD mice. They were cytotoxic to NOD islet cells, restricted to H-[2K.sup.d], and showed a diverse T cell receptor [Beta] chain repertoire. In contrast, their [Alpha] chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity-determining region 3 loop and a prevalence of V[Alpha]17 family members frequently joined to the J[Alpha]42 gene segment. These results suggest that a number of the [CD8.sup.+] T cells participating in the initial phase of autoimmune [Beta] cell destruction recognize a common structural component of [K.sup.d]/peptide complexes on pancreatic [Beta] cells, possibly a single peptide.