Increased BMN 673 chemical structure levels of TGF-β expression contribute to the enhanced suppressor function of CD62LhiFoxP3+Tregs versus CD62LloFoxP3+Tregs 7. CD62LloFoxP3+Tregs are thought to reflect an activated phenotype characterized by increased cycling 21–23. Importantly, our group and others have previously shown that the frequency of suppressive CD62LhiFoxP3+Tregs decline with age in NOD female mice which corresponds with the progression of β-cell autoimmunity 7, 24. The critical events that induce and maintain the frequency of CD62LhiFoxP3+Tregs, however, are poorly understood. Recent studies have demonstrated that IL-2 plays a key role in the maintenance

of FoxP3+Tregs homeostasis 25, 26. Mice lacking or having reduced expression of the Il2 gene develop severe, systemic autoimmunity due to the reduction of FoxP3+Tregs 27, 28. Furthermore, Sakaguchi and co-workers showed that diabetes is exacerbated in NOD mice when treated with a neutralizing Ab specific for IL-2 at an early age 29. Also, IL-2 in combination with TGF-β is important

for the differentiation of naïve CD4+ T cells into adaptive FoxP3+Tregs in vitro 30, 31. More than 20 Selleckchem Palbociclib chromosomal loci, termed insulin-dependent diabetes (Idd) regions, are associated with T1D susceptibility and resistance 32, 33. While no one gene is sufficient for the development of diabetes, the combined effects of susceptibility genes influence the progression of β-cell autoimmunity 32, 33. NOD mice congenic for the Idd3 locus derived from diabetes-resistant mouse strains exhibit a reduced incidence and delayed onset of T1D 34–37. Idd3 contains genes encoding immunoregulatory molecules including IL-2 and IL-21 34–37. The NOD Idd3 locus has been associated with reduced IL-2 expression by T cells and an aberrant FoxP3+Tregs pool 37, 38. These findings suggest that T1D is influenced by dysregulation of IL-2 expression, which leads to reduced

FoxP3+Tregs frequency and/or function found in NOD mice. In the current study, NOD mice congenic for a resistant Idd3 interval derived from C57BL/6 mice (NOD.B6Idd3) were used to further define the role of IL-2 in regulating the peripheral FoxP3+Tregs pool. We present evidence that reduced IL-2 expression tuclazepam leads to temporal dysregulation of the ratio between suppressor-deficient CD62LloFoxP3+Tregs and suppressor-competent CD62LhiFoxP3+Tregs, resulting in a pool of FoxP3+Tregs insufficient to regulate β-cell autoimmunity. Studies have demonstrated that Idd3 in NOD mice contributes to the progression of β-cell autoimmunity by influencing the pool of FoxP3+Tregs 37, 38. To further study the effect(s) of Idd3 on FoxP3+Tregs, NOD.B6Idd3 mice congenic for an ∼17 Mb interval derived from the c57a/b genotype were employed (Supporting Information Table 1). This line of NOD.