Reduced IL-2 expression in NOD mice leads to a temporal increase in CD62Llo FoxP3+ 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(+) Tregs). 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(+) Tregs and pathogenic T effectors exists. We investigated the contribution of IL-2 to dysregulation of FoxP3(+) Tregs 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). Although NOD mice exhibited a progressive decline in the frequency of CD62L(hi) FoxP3(+) Tregs due to an increase in CD62L(lo) FoxP3(+) Tregs, CD62L(hi) FoxP3(+) Tregs were maintained in the pancreatic lymph nodes and islets of NOD.B6Idd3 mice. Notably, the frequency of proliferating CD62L(hi) FoxP3(+) Tregs was elevated in the islets of NOD.B6Idd3 versus NOD mice. Increasing levels of IL-2 in vivo also resulted in larger numbers of CD62L(hi) FoxP3(+) Tregs in NOD mice. These results demonstrate that IL-2 influences the suppressor activity of the FoxP3(+) Tregs pool by regulating the balance between CD62L(lo) and CD62L(hi) FoxP3(+) Tregs. In NOD mice, reduced IL-2 expression leads to an increase in nonsuppressive CD62L(lo) FoxP3(+) Tregs, which in turn correlates with a pool of CD62L(hi) FoxP3(+) Tregs with limited proliferation.