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 () and Ming O. Li ()
Additional contact information
Weiming Ouyang: Immunology Program, Memorial Sloan-Kettering Cancer Center
Will Liao: Cold Spring Harbor Laboratory
Chong T. Luo: Immunology Program, Memorial Sloan-Kettering Cancer Center
Na Yin: Immunology Program, Memorial Sloan-Kettering Cancer Center
Morgan Huse: Immunology Program, Memorial Sloan-Kettering Cancer Center
Myoungjoo V. Kim: Immunology Program, Memorial Sloan-Kettering Cancer Center
Min Peng: Immunology Program, Memorial Sloan-Kettering Cancer Center
Pamela Chan: Immunology Program, Memorial Sloan-Kettering Cancer Center
Qian Ma: Immunology Program, Memorial Sloan-Kettering Cancer Center
Yifan Mo: Cold Spring Harbor Laboratory
Dies Meijer: Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands
Keji Zhao: Systems Biology Center, NHLBI, National Institute of Health
Alexander Y. Rudensky: Immunology Program, Memorial Sloan-Kettering Cancer Center
Gurinder Atwal: Cold Spring Harbor Laboratory
Michael Q. Zhang: Center for Systems Biology, The University of Texas at Dallas
Ming O. Li: Immunology Program, Memorial Sloan-Kettering Cancer Center

Nature, 2012, vol. 491, issue 7425, 554-559

Abstract: 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 Tregcell 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.

Date: 2012
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DOI: 10.1038/nature11581

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