Autoimmune diabetes as a consequence of locally produced interleukin-2

DURING cell differentiation in the thymus, self-reactive T cells can be generated. The majority of these seem to be deleted after intrathymic encounter with the relevant autoantigen 1 . As all self antigens are unlikely to be present in the thymus, some autoreactive T cells may escape censorship. Here we study the fate of these cells using transgenic mice expressing the class I molecule H–2K b (K b ) in the insulin-producing β -cells of the pancreas 2,3 . These mice were crossed with mice transgenic for genes encoding a K b -specific T-cell antigen receptor (TCR) 4 which could be detected using a clonotype-specific monoclonal antibody 5 . Although T cells expressing the highest level of transgenic TCR were deleted intrathymi-cally in double-transgenic mice, K b -specific T cells were detected in the periphery. These cells caused the rejection of K b -expressing skin grafts, but ignored islet K b antigens even after priming. But when double-transgenic mice were crossed with transgenic mice expressing the lymphokine interleukin-2 in the pancreatic β-cells 6 , there was a rapid onset of diabetes. These results indicate that autoreactive T cells that ignore self antigens may cause autoimmune diabetes when provided with exogenous 'help' in the form of interleukin-2.