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)beta-TGF-beta receptor signals are critical for CD4(+)CD25(+) Treg cell regulation of autoreactive islet-specific cytotoxic T lymphocytes. Transgenic expression of tumor necrosis factor a from birth to 25 days of age in the islets of B6 mice that constitutively express CD80 on their beta cells results in accumulation of CD4(+)CD25(+)TGF-beta(+) cells exclusively in the islets and pancreatic lymph nodes, which delays diabetes progression. In contrast, expression of tumor necrosis factor a until 28 days of age prevents islet accumulation of CD4(+)CD25(+)TGF-beta(+) Treg cells, resulting in acceleration to diabetes. Furthermore, adoptive transfer experiments demonstrated that CD4(+)CD25(+) Treg cells could not control naive or activated islet-reactive CD8(+) T cells bearing a dominant negative TGF-beta receptor type II. Our data demonstrate that, in vivo, TGF-beta signaling in CD8+ T cells is critical for CD4(+)CD25(+) Treg cell suppression of islet-reactive CD8(+) T cells in type 1 diabetes.