Dynamic transcriptional activity and chromatin remodeling of regulatory T cells after varied duration of interleukin-2 receptor signaling

Regulatory T cells (Tregs) require (interleukin-2) IL-2 for their homeostasis by affecting their proliferation, survival, and activation. Here we investigated transcriptional and epigenetic changes after acute, periodic, and persistent IL-2 receptor (IL-2R) signaling in murine peripheral Tregs in vivo using IL-2 or the long-acting IL-2-based biologic mouse IL-2/CD25. We show that initially IL-2R-dependent STAT5 transcription factor-dependent pathways enhanced gene activation, chromatin accessibility, and metabolic reprogramming to support Treg proliferation. Unexpectedly, at peak proliferation, less accessible chromatin prevailed and was associated with Treg contraction. Restimulation of IL-2R signaling after contraction activated signature IL-2-dependent genes and others associated with effector Tregs, whereas genes associated with signal transduction were down-regulated to somewhat temper expansion. Thus, IL-2R-dependent Treg homeostasis depends in part on a shift from more accessible chromatin and expansion to less accessible chromatin and contraction. Mouse IL-2/CD25 supported greater expansion and a more extensive transcriptional state than IL-2 in Tregs, consistent with greater efficacy to control autoimmunity.