Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7

J Immunol. 2004 May 1;172(9):5149-53. doi: 10.4049/jimmunol.172.9.5149.

Abstract

CD4(+)CD25(+) regulatory cells are a subpopulation of T lymphocytes of thymic origin. However, recent data suggest an alternative commitment of regulatory T cells in the periphery, although the precise mechanism is unknown. In the present work, we demonstrate that TGF-beta is able to induce Foxp3 expression and subsequently a regulatory phenotype in CD4(+)CD25(-) peripheral murine T cells. Similarly, TGF-beta induced Foxp3 in human CD4(+)CD25(-) T cells. Moreover, we show that the inhibitory Smad7 protein that is normally induced by TGF-beta and limits TGF-beta signaling, is strongly down-regulated by Foxp3 at the transcriptional level. Foxp3-mediated down-regulation of Smad7 subsequently rendered CD4(+)CD25(-) T cells highly susceptible to the morphogenic and regulatory effects of TGF-beta signaling via Smad3/4. In summary, we demonstrate that TGF-beta induces a regulatory phenotype in CD4(+)CD25(-) T cells through the induction of Foxp3 and a positive autoregulatory loop of TGF-beta signaling due to the absence of Smad7.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology
  • Cells, Cultured
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / physiology
  • Down-Regulation / immunology*
  • Forkhead Transcription Factors
  • Humans
  • Immunophenotyping*
  • Mice
  • Receptors, Interleukin-2* / metabolism
  • Signal Transduction / immunology
  • Smad7 Protein
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / physiology
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / physiology*

Substances

  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Interleukin-2
  • SMAD7 protein, human
  • Smad7 Protein
  • Smad7 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta