Development of type I diabetes requires coordinated expression of myriad genes responsible for the initiation and progression of the disease. Expression of these genes are regulated by a small number of transcription factors including the Rel/NF-кB family. To determine the roles of the Rel/NF-кB family in type I diabetes, we studied multiple low-dose streptozotocin-induced diabetes in mice deficient in either c-Rel or NF-кB1. We found that mice deficient in each of these NF-кB subunits were resistant to streptozotocin-induced diabetes. However, the mechanisms of the disease resistance may differ in different cases. Deficiency in c-Rel selectively reduced Th1, but not Th2 responses, whereas NF-кB1 deficiency had little effect on T cell responses to anti-CD3 stimulation. Death of dendritic cells was accelerated in the absence of NF-кB1, whereas death of macrophages and granulocytes was affected primarily by c-Rel deficiency. Furthermore, Stat-1 expression was significantly reduced in macrophages deficient in NF-кB1, but not c-Rel. These results indicate that both c-Rel and NF-_B1are essential for the development of type I diabetes and that strategies targeting each of these subunits would be effective in preventing the disease.

TRAIL, the tumor necrosis factor-related apoptosis-inducing ligand, selectively induces apoptosis of tumor cells, but not most normal cells. Its role in normal, nontransformed tissues is not clear. We report here that mice deficient in TRAIL have a severe defect in thymocyte apoptosis-thus, thymic deletion induced by T cell receptor ligation is severely impaired. TRAIL-deficient mice are also hypersensitive to collagen-induced arthritis and streptozotocin-induced diabetes and develop heightened autoimmune responses.Thus,TRAIL mediates thymocyte apoptosis and is important in the induction of autoimmune diseases.