Reduced IL-2 expression in NOD mice leads to a temporal increase in CD62LloFoxP3+CD4+ T cells with limited suppressor activity

IL-2 plays a critical role in the induction and maintenance of FoxP3-expressing regulatory T cells (FoxP3+Treg). Reduced expression of IL-2 is linked to T cell-mediated autoimmune diseases such as Type 1 diabetes (T1D), in which an imbalance between FoxP3+Treg and pathogenic T effectors exists. We investigated the contribution of IL-2 to dysregulation of FoxP3+Treg by comparing wildtype NOD mice with animals congenic for a C57BL/6-derived disease resistant Il2 allele and in which T cell secretion of IL-2 is increased (NOD.B6Idd3). Whereas NOD mice exhibited a progressive decline in the frequency of CD62LHIFoxP3+Treg due to an increase in CD62LLOFoxP3+Treg, CD62LHIFoxP3+Treg were maintained in the pancreatic lymph nodes and islets of NOD.B6Idd3 mice. Notably, the frequency of proliferating CD62LHIFoxP3+Treg was elevated in the islets of NOD.B6Idd3 versus NOD mice. Increasing levels of IL-2 in vivo also resulted in larger numbers of CD62LHIFoxP3+Treg in NOD mice. These results demonstrate that IL-2 influences the suppressor activity of the FoxP3+Treg pool by regulating the balance between CD62LLO and CD62LHI FoxP3+Treg. In NOD mice reduced IL-2 expression leads to an increase in nonsuppressive CD62LLOFoxP3+Treg, which in turn correlates with a pool of CD62LHIFoxP3+Treg with limited proliferation