Regulatory T cells can mediate their function through the stimulation of APCs to produce immunosuppressive nitric oxide.

Regulatory T cells (Tr cells) play a critical role in inducing immune tolerance. It remains largely unclear how various types of Tr cells perform their regulatory function. We have studied the underlying regulatory mechanism of a population of autoantigen-specific CD4+ Tr cells. These T cells are specific for the glutamic acid decarboxylase p206-220 peptide and are isolated from the diabetes-resistant nonobese-resistant mice. Although these T cells express T-bet and display a Th1 phenotype, they are able to inhibit diabetes. Their regulatory function is dependent on both IFN-gamma and cell contact with target cells. These Tr cells can mediate their cell contact-dependent regulatory function by secreting IFN-gamma which stimulates APCs to produce NO. NO is necessary for the Tr cells to inhibit the proliferation of pathogenic T cells and the development of diabetes. Therefore, we have identified a novel mechanism by which these Tr cells can exert their regulatory function. These results also provide an explanation as to why IFN-gamma may play both pathogenic and immunomodulatory roles in autoimmune diseases.