Transcriptional control of IL-2 sensing by Foxo1 dictates neonatal Treg homeostasis

Regulatory T (Treg) cells are essential for immune tolerance and include thymic- and peripherally-derived subsets. Among thymic-derived Treg cells, those generated perinatally are phenotypically and functionally distinct from adult cells, with superior capacity to prevent autoimmunity. However, the mechanisms controlling their peripheral seeding remain unclear. Here, we show that the transcription factor Foxo1 is critical for neonatal Treg cell homeostasis rather than for the generation of thymic- or peripherally-derived subsets. Using Foxo1-deficient mice, we demonstrate that Foxo1 deficiency profoundly impairs seeding and expansion of neonatal Tregs in secondary lymphoid organs, disrupting the overall Treg cell compartment. This defect is linked to reduced IL-2 receptor β-chain (IL-2Rβ/CD122) expression, diminished STAT5 activation, and impaired IL-2 responsiveness. Mechanistically, Foxo1 directly binds the Il2rb promoter, fine-tuning its transcription. These findings establish Foxo1 as a central regulator of IL-2-mediated signaling and neonatal Treg cell homeostasis, ensuring proper subset heterogeneity, and long-term immune tolerance. One Sentence Summary : Foxo1 safeguards neonatal Treg cell homeostasis by directly controlling IL-2 receptor β-chain expression, thereby ensuring proper IL-2 responsiveness, peripheral seeding, and expansion of this critical subset.