Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes

We thank Thomas et al. (1) for their insightfulcomments regarding the functional dynamicsof CD4Foxp3 regulatory T-cells (Tregs) intheir model of type 1 diabetes. An impressive array of studies in the literature establishes that CD4Foxp3 Tregs play a central, master-switch role in peripheral tolerance in the NOD mouse model of sponta-neous type 1 diabetes (2,3). A central question is whether the onset of spontaneous disease in NOD mice results from a decline in regulation over time or from uncontrol-lable activity of self-reactive T-cells. Type 1 diabetes may reflect subtle, functional deficiencies in regulatory T-cells, thus allowing the diabetogenic process to unfold. In our study (4), we attempted to determine whether temporal, quantitative, or qualitative defects in CD4Foxp3 Tregs contribute to spontaneous type 1 diabetes. The BDC2.5 mouse model contains a highly pathogenic CD4 T-cell repertoire and represents a unique system t