A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells

Nat Immunol. 2012 Oct;13(10):972-80. doi: 10.1038/ni.2420. Epub 2012 Sep 9.


The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3(+)CD4(+) regulatory T cells (T(reg) cells) but is neither strictly necessary nor sufficient to determine the characteristic T(reg) cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T(reg) cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T(reg) cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T(reg) cell phenotype, a model that would account for several aspects of T(reg) cell physiology, differentiation and stability.

Publication types

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

MeSH terms

  • Animals
  • CD4 Antigens / biosynthesis
  • Cell Differentiation
  • Computational Biology
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Forkhead Transcription Factors / genetics
  • GATA1 Transcription Factor / genetics
  • Humans
  • Ikaros Transcription Factor / biosynthesis
  • Ikaros Transcription Factor / genetics
  • Interferon Regulatory Factors / genetics
  • Lymphocyte Activation
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Matrix Attachment Region Binding Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Regulatory Factor X Transcription Factors
  • Serine Endopeptidases / genetics
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • X-Box Binding Protein 1


  • CD4 Antigens
  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • IKZF2 protein, human
  • Interferon Regulatory Factors
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Matrix Attachment Region Binding Proteins
  • Regulatory Factor X Transcription Factors
  • SATB1 protein, human
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • interferon regulatory factor-4
  • Ikaros Transcription Factor
  • EOS serine protease, human
  • Serine Endopeptidases

Associated data

  • GEO/GSE13306
  • GEO/GSE40278
  • GEO/GSE7460
  • GEO/GSE7596
  • GEO/GSE7852