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Regulatory T cells appear to show great potential for use in cellular therapy. In particular, CD4 À CD8 À (double negative (DN)) T cells, which compose 1-3% of the total number of T lymphocytes, exhibit prominent antigen-specific immune tolerance properties and confer immune tolerance in models of allografts and xenografts. We have recently shown that autoimmunediabetes-prone mice carry fewer DN T cells and that this phenotype contributes to autoimmune-prone diabetes susceptibility, suggesting that increasing DN T-cell number in autoimmune-prone individuals may be of therapeutic interest. To achieve this goal, we must first determine whether the remaining DN T cells in autoimmune-prone mice are functional. In addition, we must identify the parameters that regulate the numbers of DN T cells. Herein, we evaluate the immunoregulatory properties of DN T cells in the autoimmune-prone non-obese diabetic (NOD) genetic background. Using 3A9 TCR transgenic mice, we show that DN T cells from both diabetes-resistant B10.Br and genetically autoimmune-prone NOD.H2 k mice show an equivalent immunoregulatory potential on a per cell basis. However, upon stimulation, there is a 10-fold increase in the number of 3A9 TCR transgenic DN T cells that produce interleukin10 (IL-10) from NOD.H2 k mice in comparison with B10.Br mice. We further showed that IL-10 facilitates DN T-cell apoptosis and thus may regulate the number of DN T cells. Taken together, our results show that, although reduced in number, DN T cells from mice carrying an autoimmune-prone genetic background exhibit a potent cytotoxic potential and that DN T-cell expansion is regulated, at least in part, by IL-10.

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