FOXP-stabilization of the Il2ra super-enhancer structure augments Treg fitness

Gene expression in regulatory T cells (Tregs) is context-dependent and maintains peripheral immune homeostasis. FOXP3 is lineage defining but not sufficient for Treg function or persistence. To define the cell-intrinsic roles of the FOXP3 paralogs FOXP1 and FOXP4, we generated and studied mice with Treg-specific deletion of Foxp1 and/or Foxp4 . FOXP1 and FOXP4 are required to maintain the peripheral Treg pool through enhancing Il2ra transcription, thereby promoting sustained high-level expression of IL-2Rα and thus of the high-affinity IL-2Rαβγ complex. Integrating RNA-seq and ATAC-seq with previously published ChIA-PET and publicly available data, we propose a model of Il2ra transcriptional regulation in which in which FOXP1 and FOXP4 anchor chromatin looping of the Il2ra locus in mature Tregs, augment super-enhancer activity, and drive sustained CD25 expression. Our results reveal a unique role of FOXP1, and to a lesser extent FOXP4, in controlling Treg homeostasis. One Sentence Summary FOXP1 and FOXP4 regulate chromatin architecture at the Il2ra locus, promoting sustained CD25 expression and maintaining the peripheral Treg pool.