Regulatory T (T_reg) cells 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 mouse peripheral T_reg cells 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 T_reg cell proliferation. Unexpectedly, at peak proliferation, less accessible chromatin prevailed and was associated with T_reg cell contraction. Restimulation of IL-2R signaling after contraction activated signature IL-2-dependent genes and others associated with effector T_reg cells, whereas genes associated with signal transduction were downregulated to somewhat temper expansion. Thus, IL-2R-dependent T_reg cell 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 T_reg cells, consistent with greater efficacy to control autoimmunity.

调节性 T (T _reg ) 细胞需要 (interleukin-2) IL-2 通过影响其增殖、存活和激活来保持体内平衡。在这里，我们使用 IL-2 或基于 IL-2 的长效生物小鼠 IL-2 在体内研究了小鼠外周 T _reg细胞中急性、周期性和持续性 IL-2 受体 (IL-2R) 信号传导后的转录和表观遗传变化。 –CD25。我们发现，最初 IL-2R 依赖性 STAT5 转录因子依赖性途径增强了基因激活、染色质可及性和代谢重编程，以支持 T _reg细胞增殖。出乎意料的是，在增殖高峰时，染色质不易接近，并且与 T _reg细胞收缩有关。收缩后重新刺激 IL-2R 信号激活了标志性 IL-2 依赖性基因和其他与效应 T _reg细胞相关的基因，而与信号转导相关的基因则被下调，从而在一定程度上调节了扩张。因此，IL-2R 依赖性 T _reg细胞稳态部分取决于从更易接近的染色质和扩张到更难接近的染色质和收缩的转变。小鼠 IL-2–CD25 在 T _reg细胞中支持比 IL-2 更大的扩增和更广泛的转录状态，这与控制自身免疫的更大功效一致。