Abstract
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 Foxp3DTR 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.
Highlights
Type 1 diabetes (T1D) is a chronic disease under complex environmental, immunological and genetic control, which is manifested by the autoimmune destruction of functional insulinproducing b cells of pancreatic islets caused by islet-infiltrating diabetogenic CD4+ and CD8+ T cells [1, 2]
We show that the specific ablation of Foxp3+ Treg cells in DEREG mice can reproducibly precipitate severe insulitis and stable hyperglycemia in the context of a polyclonal T cell receptor (TCR) repertoire, provided that the autoimmune susceptibility is preinstalled by the NOD genetic background
The reappearance of Foxp3+ Treg cells shortly after withdrawal of DT has been observed in other Foxp3DTR lines [8, 45], including Foxp3BAC-diphtheria toxin receptor (DTR)/GFP mice [9], but the apparent differences in the depletion efficiency and recovery kinetics between mouse lines indicate that the DEREG model is suitable for studies on the Treg cell-mediated control of organ-specific autoimmune responses [26]
Summary
Type 1 diabetes (T1D) is a chronic disease under complex environmental, immunological and genetic control, which is manifested by the autoimmune destruction of functional insulinproducing b cells of pancreatic islets caused by islet-infiltrating diabetogenic CD4+ and CD8+ T cells [1, 2]. Foxp3-deficient scurfy mice on the diabetes-prone NOD background (NOD.Foxp3sf) develop exocrine pancreatitis and peri-insulitis, but do not develop insulitis and overt diabetes, unless the CD4+ T cell receptor (TCR) repertoire of NOD.Foxp3sf mice is artificially restricted to a single highly diabetogenic specificity by transgenic expression of the BDC2.5 TCR [11] These observations could be interpreted as evidence that Foxp3+ Treg cells are dispensable for the autoimmune b cell protection in the NOD model, but the interpretation of data in the constitutive absence of Treg cells is hampered by potentially confounding effects of immune adaptations and severe systemic autoimmunity, including premature death and alterations in thymic T cell development [12]. These limitations in specificity and efficiency of CD25-targeted interference with Foxp3+ Treg cell activity may account for the largely contradictory range of data in the NOD model, including precipitation of overt diabetes [16,17,18,19], accelerated diabetes progression in young but not adult mice [20], as well as maintenance of b cell tolerance [21,22,23], or even delayed onset of diabetes [22]
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