Type I diabetes (T1D) susceptibility is inherited through multiple insulin-dependent diabetes (Idd) genes. NOD. B6 Idd3 congenic mice, introgressed with an Idd3 allele from T1D-resistant C57BL/6 mice (Idd3 B6), show a marked resistance to T1D compared with control NOD mice. The protective function of the Idd3 locus is confined to the Il2 gene, whose expression is critical for naturally occurring CD4+ Foxp3+ regulatory T (nT reg) cell development and function. In this study, we asked whether Idd3 B6 protective alleles in the NOD mouse model confer T1D resistance by promoting the cellular frequency, function, or homeostasis of nT reg cells in vivo. We show that resistance to T1D in NOD. B6 Idd3 congenic mice correlates with increased levels of IL-2 mRNA and protein production in Ag-activated diabetogenic CD4+ T cells. We also observe that protective IL2 allelic variants (Idd3 B6 resistance allele) also favor the expansion and suppressive functions of CD4+ Foxp3+ nT reg cells in vitro, as well as restrain the proliferation, IL-17 production, and pathogenicity of diabetogenic CD4+ T cells in vivo more efficiently than control do nT reg cells. Lastly, the resistance to T1D in Idd3 congenic mice does not correlate with an augmented systemic frequency of CD4+ Foxp3+ nT reg cells but more so with the ability of protective IL2 allelic variants to promote the expansion of CD4+ Foxp3+ nT reg cells directly in the target organ undergoing autoimmune attack. Thus, protective, IL2 allelic variants impinge the development of organ-specific autoimmunity by bolstering the IL-2 producing capacity of self-reactive CD4+ T cells and, in turn, favor the function and homeostasis of CD4+ Foxp3+ nT reg cells in vivo.