Novel Foxo1-dependent transcriptional programs control Treg cell function

Weiming Ouyang, Will Liao, Chong T. Luo, Na Yin, Morgan Huse, Myoungjoo V. Kim, Min Peng, Pamela Chan, Qian Ma, Yifan Mo, Dies Meijer, Keji Zhao, Alexander Y. Rudensky, Gurinder Atwal, Michael Q. Zhang, Ming O. Li

Research output: Contribution to journalArticlepeer-review

Abstract

Regulatory T (Treg) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses1, 2, 3, 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, 7, 8, 9, 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 that seen in 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 pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt–Foxo1 signalling module controls a novel genetic program indispensable for Treg cell function.
Original languageEnglish
Pages (from-to)554-559
JournalNature
Volume491
Issue number7425
DOIs
Publication statusPublished - 22 Nov 2012

Fingerprint

Dive into the research topics of 'Novel Foxo1-dependent transcriptional programs control Treg cell function'. Together they form a unique fingerprint.

Cite this