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

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Animal, Autoimmunity, CD4-Positive-T-Lymphocytes, CD8-Positive-T-Lymphocytes, Cell-Division, Clone-Cells, Diabetes-Mellitus-Insulin-Dependent, Genetic-Predisposition-to-Disease, Genetic-Vectors, Lymphocytic-Choriomeningitis-Virus, Mice, Mice-Inbred-NOD, Mice-Transgenic, Stem-Cells, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, T-Lymphocytes, Transgenes

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Diabetes 2001 Sep; 50(9):1992-2000.


A broad repertoire of pancreatic beta-cell autoreactive T-cells normally contributes to the development of type 1 diabetes in NOD mice. However, it has been unknown if a large reduction in the precursor pool from which autoreactive 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 expression of an H2-Db class I-restricted T-cell receptor (TCR) specific for a pathologically irrelevant lymphocytic choriomeningitis virus (LCMV) peptide. TCR allelic exclusion greatly reduced the pool of T-cells from which diabetogenic effectors could be derived in these NODxLCMV TCR Tg mice. Surprisingly, this did not impair their type 1 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 NODxLCMV TCR Tg mice. Other data indicated that the antigenic specificity of these CD8 T-cells is primarily the function of a shared TCR-alpha chain. Although the percentage of TCR transgenic T-cells decreased in NOD versus B6,D2 control mice, much higher total numbers of both the TCR transgenic and the nontransgenic T-cells accumulated in the NOD strain. This transgenic T-cell accumulation in the absence of the cognate peptide indicated that the NOD genetic background preferentially promotes a highly efficient antigen-independent T-cell expansion. This might allow diabetogenic T-cells in NOD mice to undergo an efficient expansion before encountering antigen, which would represent an important and previously unconsidered aspect of pathogenesis.