Insulin-dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse results from effector T cell-mediated autoimmune processes directed against pancreatic beta cells. These effector T cell-mediated beta cell-specific autoimmune processes can be blocked by transfusion with supressor T cells. The CD4+ autoreactive T cell clone, NY4.2, isolated from lymphocytes infiltrating the pancreatic islets of NOD mice was transfused into young NOD mice and none of the animals became diabetic. Similarly, when NY4.2 cells were transfused into acutely diabetic NOD mice prior to syngeneic islet transplantation, the grafted islets were not destroyed and the animals maintained normoglycaemia. This investigation was initiated to determine how our cloned CD4+ autoreactive suppressor T cells are able to inhibit effector T cell-mediated beta cell destruction in NOD mice. We found that NY4.2 cells, which responded to self MHC class II determinants, had a significant immunosuppressive effect on proliferative responses of splenic effector T cells from NOD mice. This suppressive activity of the NY4.2 cells was a result of soluble factors secreted by them. The clone was found to produce substantial amounts of transforming growth factor beta (TGF-beta), IL-10, and IFN-gamma, but not IL-2 or IL-4, indicating that this T cell clone is not a member of either the classic Th1 or Th2 cell type. The suppressive activity of NY4.2 cells was abrogated by treatment with anti-TGF-beta antibodies, but not by treatment with anti-IL-10 or anti-IFN-gamma antibodies. On the basis of these observations, we suggest that a new type of CD4+ suppressor T cell, NY4.2, by secreting TGF-beta, can prevent effector T cell-mediated beta cell destruction.