Several mechanisms have been proposed to explain how certain MHC class II molecules afford dominant resistance to autoimmune diseases like type 1 diabetes (T1D). However, it remains unclear how protective MHC types can blunt autoreactive T cell responses directed against a diverse repertoire of autoantigenic epitopes presented by disease-promoting MHCs. In this study, we show that expression of I-E on dendritic cells (DCs) of NOD mice promotes the differentiation of MHC promiscuous autoreactive CD4(+) clonotypes into antidiabetogenic autoregulatory T cells. We expressed an I-Eα(kloxP) transgene in NOD mice and used cell type-specific I-E ablation to show that I-E-expressing DCs, but not B cells, promote the generation of autoreactive CD4(+)Foxp3(+) regulatory T cells (Tregs) and their accumulation in the pancreas-draining lymph nodes. There, these Tregs suppress the presentation of β cell Ags to naive autoreactive CD4(+) and CD8(+) T cells restricted by diabetogenic MHC molecules in an I-E-independent manner. Whereas selective removal of I-E on DCs abrogated autoregulatory Treg formation and T1D protection, selective removal of I-E on B cells was inconsequential. These results explain how certain MHC class II molecules can completely suppress antigenically complex autoimmune responses in an Ag-nonspecific manner.