Functional impact of the protective Idd3 allele on regulatory T cells and protection from type-1 diabetes

NOD.B6 Idd3 congenic mice, whose Idd3 locus originates from the autoimmune resistant C57BL/6 mouse, demonstrate a drastic reduction in diabetes onset. In this study we demonstrate that NOD.B6 Idd3 mice show halted disease progression and also show reduced levels of TH1 cells in their peripheral immune system. In vitro , CD4+ CD25- effector T (TEFF ) cells from congenic mice display increased proliferation and IL-2 production compared to wild type NOD mice. However, unfractionated NOD.B6 Idd3 CD4+ T cells maintain a higher TREG:T EFF ratio and proliferate less than their NOD counterparts, suggesting increased immunoregulation. In vivo, the Idd3 locus does not appear to reduce the number of islet-reactive cells or increase the systemic frequency of TREG cells in the immune system of pre-diabetic mice. Instead, reduced infiltration of TEFF cells in the pancreas of NOD.B6 Idd3 mice suggests increased suppression of autoimmune cells at the site of inflammation in vivo. Consistent with this hypothesis, tolerance mechanisms in the NOD.B6 Idd3 mouse are much better at suppressing the proliferation of islet-reactive T EFF cells in the pLN. Furthermore, using a novel strain of BDC.Idd3 mice, which contain islet-reactive TCR transgenic CD4+ T cells and which are homozygous for the B6-derived Idd3 allele, we demonstrate that TEFF cells containing the protective Idd3 allele do not possess reduced diabetogenic potential in vivo. Using an adoptive transfer model for type-1 diabetes, we demonstrate that CD4+CD25+ TREG containing the protective Idd3 allele are intrinsically better suppressors than TREG cells of NOD genotype. Collectively, our data show that the protective Idd3 allele favours immunoregulation in the pancreatic lesion by enhancing TREG cell function. Although the precise mechanism of this protection remains unknown, these findings may ultimately help develop therapeutic strategies to reduce or prevent the autoimmune destruction of pancreatic beta islet cells in type-1 diabetes patients