Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells

Nat Immunol. 2010 Jul;11(7):618-27. doi: 10.1038/ni.1884. Epub 2010 May 13.


CD4(+) regulatory T cells (T(reg) cells) characterized by expression of the transcription factor Foxp3 have a pivotal role in maintaining immunological tolerance. Here we show that mice with T cell-specific deletion of both the Foxo1 and Foxo3 transcription factors (collectively called 'Foxo proteins' here) developed a fatal multifocal inflammatory disorder due in part to T(reg) cell defects. Foxo proteins functioned in a T(reg) cell-intrinsic manner to regulate thymic and transforming growth factor-beta (TGF-beta)-induced Foxp3 expression, in line with the ability of Foxo proteins to bind to Foxp3 locus and control Foxp3 promoter activity. Transcriptome analyses showed that Foxo proteins regulated the expression of additional T(reg) cell-associated genes and were essential for inhibiting the acquisition of effector T cell characteristics by T(reg) cells. Thus, Foxo proteins have crucial roles in specifying the T(reg) cell lineage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4 Antigens / biosynthesis
  • Cell Differentiation / immunology*
  • Cell Lineage
  • Cells, Cultured
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Inflammation
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mutation / genetics
  • Protein Binding
  • Regulatory Elements, Transcriptional / genetics
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology
  • Thymus Gland / immunology
  • Thymus Gland / metabolism*
  • Thymus Gland / pathology
  • Transforming Growth Factor beta / metabolism


  • CD4 Antigens
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • Foxo1 protein, mouse
  • Foxp3 protein, mouse
  • Transforming Growth Factor beta

Associated data

  • GEO/GSE21678