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Type 1 diabetes (T1D) represents a hallmark of the fatal multiorgan autoimmune syndrome affecting humans with abrogated Foxp3 +  regulatory T (Treg) cell function due to  Foxp3  gene mutations, but whether the loss of Foxp3 +  Treg cell activity is indeed sufficient to promote β cell autoimmunity requires further scrutiny. As opposed to human Treg cell deficiency, β cell autoimmunity has not been observed in non-autoimmune-prone mice with constitutive  Foxp3  deficiency or after diphtheria toxin receptor (DTR)-mediated ablation of Foxp3 +  Treg cells. In the spontaneous nonobese diabetic (NOD) mouse model of T1D, constitutive Foxp3 deficiency did not result in invasive insulitis and hyperglycemia, and previous studies on Foxp3 +  Treg cell ablation focused on Foxp3 DTR  NOD mice, in which expression of a transgenic BDC2.5 T cell receptor (TCR) restricted the CD4 +  TCR repertoire to a single diabetogenic specificity. Here we revisited the effect of acute Foxp3 +  Treg cell ablation on β cell autoimmunity in NOD mice in the context of a polyclonal TCR repertoire. For this, we took advantage of the well-established DTR/GFP transgene of DEREG mice, which allows for specific ablation of Foxp3 +  Treg cells without promoting catastrophic autoimmune diseases. We show that the transient loss of Foxp3 +  Treg cells in prediabetic NOD.DEREG mice is sufficient to precipitate severe insulitis and persistent hyperglycemia within 5 days after DT administration. Importantly, DT-treated NOD.DEREG mice preserved many clinical features of spontaneous diabetes progression in the NOD model, including a prominent role of diabetogenic CD8 +  T cells in terminal β cell destruction. Despite the severity of destructive β cell autoimmunity, anti-CD3 mAb therapy of DT-treated mice interfered with the progression to overt diabetes, indicating that the novel NOD.DEREG model can be exploited for preclinical studies on T1D under experimental conditions of synchronized, advanced β cell autoimmunity. Overall, our studies highlight the continuous requirement of Foxp3 +  Treg cell activity for the control of genetically pre-installed autoimmune diabetes.

Transient Depletion of Foxp3+ Regulatory T Cells Selectively Promotes Aggressive β Cell Autoimmunity in Genetically Susceptible DEREG Mice