title: Novel Foxo1-dependent transcriptional programs control T(reg) cell function.
abstract: Regulatory T (T(reg)) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling T(reg) cell homeostasis and function, whereas the early T(reg)-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the T(reg)-cell-commitment stage to control T(reg) cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of T(reg )cell function. T(reg) cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with T(reg)-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 T(reg) 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 T(reg) cell function.
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Ouyang
authors.forename: Will
authors.initials: W
authors.lastname: Liao
authors.forename: Chong T
authors.initials: CT
authors.lastname: Luo
authors.forename: Na
authors.initials: N
authors.lastname: Yin
authors.forename: Morgan
authors.initials: M
authors.lastname: Huse
authors.forename: Myoungjoo V
authors.initials: MV
authors.lastname: Kim
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.forename: Pamela
authors.initials: P
authors.lastname: Chan
authors.forename: Qian
authors.initials: Q
authors.lastname: Ma
authors.forename: Yifan
authors.initials: Y
authors.lastname: Mo
authors.forename: Dies
authors.initials: D
authors.lastname: Meijer
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.forename: Gurinder
authors.initials: G
authors.lastname: Atwal
authors.forename: Michael Q
authors.initials: MQ
authors.lastname: Zhang
authors.forename: Ming O
authors.initials: MO
authors.lastname: Li
mesh_terms: D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D005260:Female; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D016678:Genome / Q000235:genetics; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt