In summary, we conclude that NLRP3 inflammasome activation mediated by mitochondrial DNA from diabetic mice promotes caspase-1 activation and IL-1β production by macrophages, which drives pathogenic Th17/Tc17/Th1 responses and negatively modulates the tolerogenic responses mediated by MDSC and mast cells in the PLNs, and leads to the development of T1D. Here, NLRP3 is linked to type 1 diabetes mellitus.