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PLoS One. 2014 Feb 5;9(2):e88318. doi: 10.1371/journal.pone.0088318. eCollection 2014.

The Treg-specific demethylated region stabilizes Foxp3 expression independently of NF-κB signaling.

Author information

1
Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
2
Research Group Cellular Proteomics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
3
Research Group Systems-oriented Immunology and Inflammation Research, Helmholtz Centre for Infection Research, Braunschweig, Germany ; Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, Magdeburg, Germany.

Abstract

Regulatory T cells (Tregs) obtain immunosuppressive capacity by the upregulation of forkhead box protein 3 (Foxp3), and persistent expression of this transcription factor is required to maintain their immune regulatory function and ensure immune homeostasis. Stable Foxp3 expression is achieved through epigenetic modification of the Treg-specific demethylated region (TSDR), an evolutionarily conserved non-coding element within the Foxp3 gene locus. Here, we present molecular data suggesting that TSDR enhancer activity is restricted to T cells and cannot be induced in other immune cells such as macrophages or B cells. Since NF-κB signaling has been reported to be instrumental to induce Foxp3 expression during Treg development, we analyzed how NF-κB factors are involved in the molecular regulation of the TSDR. Unexpectedly, we neither observed transcriptional activity of a previously postulated NF-κB binding site within the TSDR nor did the entire TSDR show any transcriptional responsiveness to NF-κB activation at all. Finally, the NF-κB subunit c-Rel revealed to be dispensable for epigenetic imprinting of sustained Foxp3 expression by TSDR demethylation. In conclusion, we show that NF-κB signaling is not substantially involved in TSDR-mediated stabilization of Foxp3 expression in Tregs.

PMID:
24505473
PMCID:
PMC3914969
DOI:
10.1371/journal.pone.0088318
[Indexed for MEDLINE]
Free PMC Article
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