GSE40656
Novel Foxo1-dependent Transcriptional Programs Control Treg Cell Function [ChIP-Seq]
Regulatory T (Treg) cells characterized by expression of the transcription factor forkhead box P3 (Foxp3) maintain immune homeostasis by suppressing self-destructive immune responses1-4.  Foxp3 operates as a late acting differentiation factor controlling Treg cell homeostasis and function5, whereas the early Treg cell lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors6-10. However, whether Foxo proteins act beyond the Treg cell commitment stage to control Treg cell homeostasis and function remains largely unexplored.  Here we show that Foxo1 is a pivotal regulator of Treg cell function.  Treg cells express high amounts of Foxo1, and display reduced T-cell receptor-induced Akt activation, Foxo1 phosphorylation, and Foxo1 nuclear exclusion.  Mice with Treg cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to Foxp3-deficient mice, but without the loss of Treg cells.  Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the proinflammatory cytokine Ifng, that do not appear to be directly regulated by Foxp3.  These findings demonstrate that the evolutionarily ancient Akt-Foxo1 signaling module controls a novel genetic program indispensable for Treg cell function. Overall design: Treg cells were isolated from wild-type B6 mice or Foxo1tagBirA mice in which foxo1 is endogenously biotinylated. Foxo1 binding targets in Treg cells were identified by using Foxo1 antibody- and Streptavidin- ChIP-Seq approaches.