Novel Foxo1-dependent Transcriptional Programs Control Treg Cell Function [Affymetrix gene expression data]

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.

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