Autoreactive diabetogenic T-cells in NOD mice can efficiently expand from a greatly reduced precursor pool

A broad repertoire of pancreatic beta -cell autoreactive T-cells normally c ontributes to the development of type I diabetes in NOD mice. However, it h as been unknown if a large reduction in the precursor pool from which autor eactive T-cells are drawn would inhibit the development of type 1 diabetes. To address this issue, we reduced the precursor frequency of autoreactive T-cells in NOD mice through allelic exclusion induced by transgenic express ion of an H2-D-b class I-restricted T-cell receptor (TCR) specific for a pa thologically irrelevant lymphocytic choriomeningitis virus (LCMV) peptide. TCR allelic exclusion greatly reduced the pool of T-cells from which diabet ogenic effectors could be derived in these NOD.LCMV TCR Tg mice. Surprising ly, this did not impair their type I diabetes susceptibility. Furthermore, a diabetogenic CD8 T-cell population that is prevalent in standard NOD mice was present at essentially equivalent levels in pancreatic islets of NOD.L CMV TCR Tg mice. Other data indicated that the antigenic specificity of the se CD8 T-cells is primarily the function of a shared TCR-a chain. Although the percentage of TCR transgenic T-cells decreased in NOD versus B6,D2 cont rol mice, much higher total numbers of both the TCR transgenic and the nont ransgenic T-cells accumulated in the NOD strain. This transgenic T-cell acc umulation in the absence of the cognate peptide indicated that the NOD gene tic background preferentially promotes a highly efficient antigen-independe nt T-cell expansion. This might allow diabetogenic T-cells in NOD mice to u ndergo an efficient expansion before encountering antigen, which would repr esent an important and previously unconsidered aspect of pathogenesis.