CD4+CD25+T Regulatory Cells Control Anti-Islet CD8+T Cells through TGF-β-TGF-β Receptor Interactions in Type 1 Diabetes

Pancreatic lymph node-derived CD4+CD25+T regulatory (Treg) cells inhibit in situ differentiation of islet-reactive CD8+T cells into cytotoxic T lymphocytes, thereby preventing diabetes progression. The mechanism by which these Treg cells suppress anti-islet CD8+T cells is unknown. Here, we show by using a CD8+T cell-mediated model of type 1 diabetes that transforming growth factor (TGF)-β-TGF-β receptor signals are critical for CD4+CD25+Treg cell regulation of autoreactive islet-specific cytotoxic T lymphocytes. Transgenic expression of tumor necrosis factor α from birth to 25 days of age in the islets of B6 mice that constitutively express CD80 on their β cells results in accumulation of CD4+CD25+TGF-β+cells exclusively in the islets and pancreatic lymph nodes, which delays diabetes progression. In contrast, expression of tumor necrosis factor α until 28 days of age prevents islet accumulation of CD4+CD25+TGF-β+Treg cells, resulting in acceleration to diabetes. Furthermore, adoptive transfer experiments demonstrated that CD4+CD25+Treg cells could not control naı̈ ve or activated islet-reactive CD8+T cells bearing a dominant negative TGF-β receptor type II. Our data demonstrate that, in vivo, TGF-β signaling in CD8+T cells is critical for CD4+CD25+Treg cell suppression of islet-reactive CD8+T cells in type 1 diabetes.