Diabetes in nonobese diabetic (NOD) mice is an autoimmune disease characterized by the destruction of the beta cells in the pancreas. We have previously reported that transgenic expression of interleukin-4 (IL-4) counterregulates the disease process, completely protecting NOD mice from insulitis and diabetes. Here we demonstrate the presence of autoreactivity but lack of pathogenicity of the IL-4-regulated lymphocytes. The importance of T cell diversity for the protective effect of IL-4 is demonstrated through breeding with transgenic BDC2.5 mice, which have an almost exclusively monoclonal T cell repertoire. Limitation of T cell diversity abrogated the protection by IL-4. We suggest that "immune deviation" in NOD-IL-4 mice is mediated by the pancreatic tissue itself, which causes activation of distinct, nonpathogenic T cell specificities.