The transcription factor musculin promotes the unidirectional development of peripheral T reg cells by suppressing the T H 2 transcriptional program

Nat Immunol. 2017 Mar;18(3):344-353. doi: 10.1038/ni.3667. Epub 2017 Jan 23.

Abstract

Although master transcription factors (TFs) are key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress the development of other, non-specific T cell lineages has not been fully elucidated. Through the use of regulatory T cells (Treg cells) induced by transforming growth factor-β (TGF-β), we identified the TF musculin (MSC) as being critical for the development of induced Treg cells (iTreg cells) by repression of the T helper type 2 (TH2) transcriptional program. Loss of MSC reduced expression of the Treg cell master TF Foxp3 and induced TH2 differentiation even under iTreg-cell-differentiation conditions. MSC interrupted binding of the TF GATA-3 to the locus encoding TH2-cell-related cytokines and diminished intrachromosomal interactions within that locus. MSC-deficient (Msc-/-) iTreg cells were unable to suppress TH2 responses, and Msc-/- mice spontaneously developed gut and lung inflammation with age. MSC therefore enforced Foxp3 expression and promoted the unidirectional induction of iTreg cells by repressing the TH2 developmental program.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Differentiation*
  • Cells, Cultured
  • Forkhead Transcription Factors / metabolism
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation
  • Inflammation* / genetics
  • Intestinal Mucosa / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pneumonia / immunology*
  • T-Lymphocytes, Regulatory / physiology*
  • Th2 Cells / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transforming Growth Factor beta / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Msc protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta