Insulin B-chain reactive CD4(+) regulatory T-cells induced by oral insulintreatment protect from type 1 diabetes by blocking the cytokine secretion and pancreatic infiltration of diabetogenic effector T-cells

The mechanism of protection from type 1 diabetes conferred by regulatory T- cells induced by oral insulin treatment of NOD mice is not well understood. We demonstrate that oral insulin feeding of NOD mice induces the function of insulin B-chain reactive CD4(+) regulatory T-cells, which compete with d iabetogenic effector T-cells for the recognition of insulin in NOD.ScSd rec ipient mice. These effector T-cells become deprived of interleukin (IL)-2 a nd interferon (IFN)-gamma and are unable to expand and migrate to the pancr eas. Type 1 diabetes-protective splenic regulatory T-cells secrete relative ly little transforming growth factor (TGF)-beta 1, suggesting that TGF-beta may not contribute to the inactivation of effector T-cells in NOD,Scid rec ipients. The observed preferential infiltration of insulin-reactive regulat ory T-cells rather than effector T-cells in the pancreas results in a nonde structive insulitis that correlates with an increased intrapancreatic expre ssion of macrophage inflammatory protein-1 beta. Thus, oral insulin therapy overcomes a deficiency in regulatory T-cells and protects against type 1 d iabetes by inducing insulin B-chain reactive regulatory T-cells to block cy tokine secretion and migration of diabetogenic effector T-cells to the panc reas. Our data emphasize that continuous oral insulin feeding over a prolon ged period is required to prevent type 1 diabetes.