Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice

Enhancement of regulatory T cell (T-reg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of T-reg cell homeostasis and function. We investigated how IL-2 pathway defects impact T-reg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD T-reg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, T-reg cell frequency was preserved through expansion of CD25(low), effector phenotype T-reg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD T-reg cells. In vivo, treatment with IL-2-anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD T-reg cells in the spleen and blood, but had reduced efficacy on lymph node T-reg cells. In contrast, NOD CD8(+) and CD4(+) effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD T-reg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2.