Epigenetic Control of the foxp3 Locus in Regulatory T Cells

By S. Floess, Jennifer Freyer, C. Siewert, U. Baron, S. Olek, J. Polansky, Kerstin Schlawe, Hyun-Dong Chang, T. Bopp, E. Schmitt and 4 more. PLoS Biology, 2007

1,298 citations recorded by the source corpus.

Compelling evidence suggests that the transcription factor Foxp3 acts as a master switch governing the development and function of CD4+ regulatory T cells (Tregs). However, whether transcriptional control of Foxp3 expression itself contributes to the development of a stable Treg lineage has thus far not been investigated. We here identified an evolutionarily conserved region within the foxp3 locus upstream of exon-1 possessing transcriptional activity. Bisulphite sequencing and chromatin immunoprecipitation revealed complete demethylation of CpG motifs as well as histone modifications within the conserved region in ex vivo isolated Foxp3+CD25+CD4+ Tregs, but not in naïve CD25−CD4+ T cells. Partial DNA demethylation is already found within developing Foxp3+ thymocytes; however, Tregs induced by TGF-β in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-β–induced Foxp3+ Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-β. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to allow the development of a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of Tregs and for the understanding of long-term cell lineage decisions.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/7af49e20f5f56976f6d9383c896fb373b65cb223

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Citations in the corpus

Differentiation of Effector CD4 T Cell Populations (2010, neutral): “Differential epigenetic modification at the Foxp3 locus between nTregs and iTregs has been observed (164, 258).”
Regulatory T Cells and Foxp3 (2011, background): “Another intronic element dubbed CNS2 [also known as Treg-specific demethylated region (TSDR)] contains a CpG island, whose methylation status was correlated with the Foxp3 expression and its stability (66, 67).”
Regulatory T Cells and Human Disease. (2020, background): “which exhibit Treg-specific DNA hypomethylation at Foxp3 and other Treg signature gene loci in FoxP3−CD25+CD4+ T cells (42, 43).”
Foxp3 instability leads to the generation of pathogenic memory T cells in vivo (2009, neutral): “In this regard, this methylation phenotype is reminiscent of what has been observed in in vitro TGF β -induced T regs (iT reg )18.”
T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR (2008, neutral): “The expression of the Foxp3 locus is intimately linked to its chromatin structure (33, 34).”
Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? (2009, background): “expression and suppressive activity when restimulated in the absence of TGF-b (Floess et al., 2007; Huehn et al., 2009).”
Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. (2009, background): “The 50 flanking region and a STAT5-responsive region in the in- tron 1 of the FOXP3 gene are critical for induction and enhance- ment of FoxP3 expression by TCR and IL-2 stimulation (Floess et al., 2007; Mantel et al., 2006; Zorn et al., 2006).”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, background): “Intriguingly, these elements remain heavily methylated in in vitro–generated iTreg cells, which do not stably express Foxp3 (65, 181, 182).”
First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. (2009, background): “The expression fades with the time either due to the intrinsic features of foxp3 gene or to the contamination of sorted Tregs with effectors [15].”
Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells (2012, result): “(a) The indicated cell populations were sorted from spleens of BALB/c Foxp3 GFP or TBmc Foxp3 GFP mice.”
The development of inflammatory TH-17 cells requires interferon-regulatory factor 4 (2007, background): “In addition, computer analysis has thus far failed to demonstrate any binding sites for IRF4 or STAT3 in the Foxp3 promoter and enhance”
Ischemia and reperfusion—from mechanism to translation (2011, background): “Previous studies have shown that Foxp3 levels are subject to epigenetic regulatio”
T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. (2012, background): “However, the phenotype of TGF-induced iTreg cells was found to be unstable upon restimulation in the absence of exogenous TGF-(Floess et al., 2007).”