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