title: The Treg-specific demethylated region stabilizes Foxp3 expression independently of NF-κB signaling.
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.
authors: Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Lisa
authors: L
authors: Schreiber
authors: Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Beate
authors: B
authors: Pietzsch
authors: Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Stefan
authors: S
authors: Floess
authors: Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Carla
authors: C
authors: Farah
authors: Research Group Cellular Proteomics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Lothar
authors: L
authors: Jänsch
authors: 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.
authors: Ingo
authors: I
authors: Schmitz
authors: Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Jochen
authors: J
authors: Huehn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D056426:Genetic Loci; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016328:NF-kappa B