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

Abstract

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 CD62LhiFoxP3+Tregs due to an increase in CD62LloFoxP3+Tregs, CD62LhiFoxP3+Tregs were maintained in the pancreatic lymph nodes and islets of NOD.B6Idd3 mice. Notably, the frequency of proliferating CD62LhiFoxP3+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 CD62LhiFoxP3+Tregs in NOD mice. These results demonstrate that IL-2 influences the suppressor activity of the FoxP3+Tregs pool by regulating the balance between CD62Llo and CD62Lhi FoxP3+Tregs. In NOD mice, reduced IL-2 expression leads to an increase in nonsuppressive CD62LloFoxP3+Tregs, which in turn correlates with a pool of CD62LhiFoxP3+Tregs with limited proliferation. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.