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Novel Foxo1-dependent transcriptional programs control T(reg) cell function.

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.

Pubmed ID: 23135404


  • Ouyang W
  • Liao W
  • Luo CT
  • Yin N
  • Huse M
  • Kim MV
  • Peng M
  • Chan P
  • Ma Q
  • Mo Y
  • Meijer D
  • Zhao K
  • Rudensky AY
  • Atwal G
  • Zhang MQ
  • Li MO



Publication Data

November 22, 2012

Associated Grants

  • Agency: NHGRI NIH HHS, Id: HG001696
  • Agency: NHGRI NIH HHS, Id: R01 HG001696
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Binding Sites
  • Cell Nucleus
  • Female
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Genome
  • Immune Tolerance
  • Interferon-gamma
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-akt
  • Receptors, Antigen, T-Cell
  • Signal Transduction
  • T-Lymphocytes, Regulatory
  • Transcription, Genetic