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In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-β-containing Protocol
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Foxp3 induces IL-4 gene silencing by affecting nuclear translocation of NFkappaB and chromatin structure

Ho-Keun Kwon1, Jae-Seon So, Chung-Goo Lee

  • 1Department of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-dong, Puk-ku, Gwangju 500-712, Republic of Korea.

Molecular Immunology
|April 9, 2008
PubMed

Insights

The transcription factor Foxp3 silences gene expression in differentiated T cells by blocking NF-kappaB activity and altering chromatin structure. This mechanism reveals how Foxp3 controls cytokine production in regulatory T cells.

Area of Science:

  • Immunology
  • Molecular Biology
  • Epigenetics

Background:

  • Foxp3 is a key marker for regulatory T cells (Tregs) essential for immune homeostasis.
  • While Foxp3's role in Treg development is established, its function in gene silencing within differentiated cells is less understood.

Purpose of the Study:

  • To investigate the mechanism by which ectopic Foxp3 expression silences gene expression in differentiated T helper 2 cells.
  • To determine if Foxp3 affects cytokine gene expression and chromatin structure in these cells.

Main Methods:

  • Ectopic expression of Foxp3 in primary T helper 2 cells.
  • Analysis of Interleukin-4 (IL-4) gene expression.
  • Assessment of NF-kappaB signaling pathway components, including IkappaBalpha stability and NF-kappaB binding to the IL-4 promoter.
  • Chromatin immunoprecipitation (ChIP) assays to evaluate histone modifications (acetylation and methylation) at the IL-4 genomic locus.

Main Results:

  • Ectopic Foxp3 expression abolished IL-4 gene expression in T helper 2 cells.
  • Foxp3 inhibited NF-kappaB nuclear translocation by stabilizing IkappaBalpha, reducing NF-kappaB binding to the IL-4 promoter.
  • Foxp3 overexpression induced an inactive chromatin state, characterized by decreased acetylated histone 3 and increased methylated histone 3 (H3K9) at the IL-4 locus.

Conclusions:

  • Foxp3 can induce gene silencing in differentiated T cells.
  • The mechanism involves the inhibition of NF-kappaB transcriptional activity.
  • Foxp3 promotes gene silencing by establishing an inactive chromatin configuration at target gene loci.

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