TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentiation

Nat Immunol. 2011 Nov 13;13(1):77-85. doi: 10.1038/ni.2154.

Abstract

Mice deficient in the adaptor Ndfip1 develop inflammation at sites of environmental antigen exposure. We show here that such mice had fewer inducible regulatory T cells (iT(reg) cells). In vitro, Ndfip1-deficient T cells expressed normal amounts of the transcription factor Foxp3 during the first 48 h of iT(reg) cell differentiation; however, this expression was not sustained. Abortive Foxp3 expression was caused by production of interleukin 4 (IL-4) by Ndfip1(-/-) cells. We found that Ndfip1 expression was transiently upregulated during iT(reg) cell differentiation in a manner dependent on transforming growth factor-β (TGF-β). Once expressed, Ndfip1 promoted degradation of the transcription factor JunB mediated by the E3 ubiquitin ligase Itch, thus preventing IL-4 production. On the basis of our data, we propose that TGF-β signaling induces Ndfip1 expression to silence IL-4 production, thus permitting iT(reg) cell differentiation.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Cell Differentiation* / drug effects
  • Cells, Cultured
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-4 / biosynthesis*
  • Interleukin-4 / genetics
  • Interleukin-4 / pharmacology
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Proteins c-jun / metabolism
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / pharmacology*
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Carrier Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Ndfip1 protein, mouse
  • Proto-Oncogene Proteins c-jun
  • Transforming Growth Factor beta
  • Interleukin-4
  • Itch protein, mouse
  • Ubiquitin-Protein Ligases