Control of the differentiation of regulatory T cells and T(H)17 cells by the DNA-binding inhibitor Id3

Nat Immunol. 2011 Jan;12(1):86-95. doi: 10.1038/ni.1965. Epub 2010 Dec 5.

Abstract

The molecular mechanisms that direct transcription of the gene encoding the transcription factor Foxp3 in CD4(+) T cells remain ill-defined. We show here that deletion of the DNA-binding inhibitor Id3 resulted in the defective generation of Foxp3(+) regulatory T cells (T(reg) cells). We identify two transforming growth factor-β1 (TGF-β1)-dependent mechanisms that were vital for activation of Foxp3 transcription and were defective in Id3(-/-) CD4(+) T cells. Enhanced binding of the transcription factor E2A to the Foxp3 promoter promoted Foxp3 transcription. Id3 was required for relief of inhibition by the transcription factor GATA-3 at the Foxp3 promoter. Furthermore, Id3(-/-) T cells showed greater differentiation into the T(H)17 subset of helper T cells in vitro and in a mouse asthma model. Therefore, a network of factors acts in a TGF-β-dependent manner to control Foxp3 expression and inhibit the development of T(H)17 cells.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Asthma / chemically induced
  • Asthma / genetics
  • Asthma / immunology
  • Asthma / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Inhibitor of Differentiation Proteins / genetics
  • Inhibitor of Differentiation Proteins / immunology
  • Inhibitor of Differentiation Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Promoter Regions, Genetic / genetics
  • Protein Binding / genetics
  • Sequence Deletion / genetics
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology
  • Th17 Cells / immunology
  • Th17 Cells / metabolism*
  • Th17 Cells / pathology
  • Transcriptional Activation / genetics
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Inhibitor of Differentiation Proteins
  • Tcf3 protein, mouse
  • Transforming Growth Factor beta1
  • Idb3 protein, mouse