Differential Roles of IL-2 Signaling in Developing Versus Mature Tregs

Abstract

CD4+ Foxp3+ regulatory T cells (Tregs) are unique in that the majority of Tregs constitutively express high levels of CD25, the main ligand binding subunit of the IL-2 receptor. Germline knockout models demonstrate that IL-2 is needed during Treg development to induce Foxp3, but the precise roles of IL-2 after Treg development are incompletely understood. We therefore generated mice in which CD25 can be inducibly deleted from Tregs after thymic development. In contrast to Treg development, we find that IL-2 is dispensable for maintaining lineage stability in mature Tregs. Continuous IL-2 signaling was needed for long term Treg survival, including among peripherally induced Tregs and tissue-resident Tregs. Despite this long-term requirement for IL-2, we found that CD25-deleted Tregs could persist for several weeks in vivo using IL-7. While the surface phenotypes of surviving Tregs resembled that of CD25lo Tregs, the majority of this population actually derived from CD25hi precursors. We also observed defects in glycolytic metabolism and suppressor function following CD25 deletion. Thus, unlike developing Tregs where the primary role of IL-2 is to initiate Foxp3 expression, mature Tregs require continuous IL-2 signaling to maintain survival and suppressor function, but not to maintain lineage stability.