We have produced a panel of islet-specific T-cell clones from nonobese diabetic (NOD) mice. These clones proliferate and make interleukin 2 in an antigen-specific manner in response to NOD antigen-presenting cells and islet cells. Most of the clones respond to islet-cell antigen from different mouse strains but only in the presence of antigen-presenting cells bearing the class II major histocompatibility complex of the NOD mouse. In vivo, the clones mediate the destruction of islet, but not pituitary, grafts. Furthermore, pancreatic sections from a disease transfer experiment with one of the clones showed a pronounced cellular infiltration and degranulation of islets in nondiabetic (CBA x NOD)F1 recipients.