c‐Rel: A pioneer in directing regulatory T‐cell lineage commitment?

Abstract

The transcription factor Foxp3 controls the differentiation and function of Treg, but the molecular mechanisms that regulate Foxp3 transcription remain elusive. In particular, signals and factors that open and remodel the Foxp3 locus and imprint developing Treg with a stable Foxp3 phenotype are largely unknown. Two reports in this issue of the European Journal of Immunology, together with recent reports published elsewhere, demonstrate that a member of the NF-jB family transcription factors, c-Rel, is required for thymic differentiation of Foxp3 1 Treg. Moreover, c-Rel is shown to regulate Foxp3 transcription directly by binding to cis-regulatory elements at the Foxp3 locus upon TCR/CD28 stimulation, including the promoter and the newly identified conserved non-coding DNA sequence harboring a ''permissive'' chromatin status in Treg precursors. These findings collectively suggest that c-Rel may act as a pioneer transcription factor in initiating Foxp3 transcription in Treg precursors in the thymus.

Modulation of STAT3 and STAT5 activity rectifies the imbalance of Th17 and Treg cells in patients with acute coronary syndrome

“…Reductions in Th1 and Th17 responses and the maintenance of Tregs have been reported after exposure to the JAK2 inhibitor TG101348 [26]. FOXP3 expression is regulated by various factors, such as Smad2/3, Runx1, STAT5, c-Rel, and DNA methylation of the CNS2 region in the FOXP3 enhancer [14,[27][28][29][30]. STAT3 binds to a silencer element within the FOXP3 locus and is associated with a reduction in Smad3 binding [20].…”

Canonical NF-κB Activation Is Essential for Epstein-Barr Virus Latent Membrane Protein 1 TES2/CTAR2 Gene Regulation

“…For example, NF-B activity may be required for the synthesis of enzymes that directly or indirectly modify chromatin, such as histone acetyl-deacetylases, methyltransferases, ubiquitin ligases, or kinases. In this fashion, NF-B may regulate the ability of other transcription factors to gain access to their DNA-binding sites (24,55). Additional MAPK pathway dependence has been described for a limited number of LMP1 TES2-affected RNAs, including IL-8 (16).…”

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 + regulatory T cells

“…Recently, several studies have demonstrated the importance of the NF-κB family member c-Rel for thymic Foxp3 induction (7). c-Rel binds directly to the Foxp3 locus, thereby initiating chromatin opening at a newly identified cis-regulatory element (CNS3) (8), concomitantly binding to further enhancer regions and the Foxp3 promoter (9).…”