Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate

By Ye Zheng, Steven Z. Josefowicz, A. Chaudhry, Xiao P. Peng, K. Forbush, Alexander Y. Rudensky. Nature, 2010

1,166 citations recorded by the source corpus.

Immune homeostasis is dependent on tight control over the size of a population of regulatory T (Treg) cells capable of suppressing over-exuberant immune responses. The Treg cell subset is comprised of cells that commit to the Treg lineage by upregulating the transcription factor Foxp3 either in the thymus (tTreg) or in the periphery (iTreg). Considering a central role for Foxp3 in Treg cell differentiation and function, we proposed that conserved non-coding DNA sequence (CNS) elements at the Foxp3 locus encode information defining the size, composition and stability of the Treg cell population. Here we describe the function of three Foxp3 CNS elements (CNS1–3) in Treg cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of Treg cells generated in the thymus and the periphery, binds c-Rel in in vitro assays. In contrast, CNS1, which contains a TGF-β–NFAT response element, is superfluous for tTreg cell differentiation, but has a prominent role in iTreg cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing Treg cells. Foxp3 binds to CNS2 in a Cbf-β–Runx1 and CpG DNA demethylation-dependent manner, suggesting that Foxp3 recruitment to this ‘cellular memory module’ facilitates the heritable maintenance of the active state of the Foxp3 locus and, therefore, Treg lineage stability. Together, our studies demonstrate that the composition, size and maintenance of the Treg cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or -intrinsic cues.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/1527f85868d541accbe393a32a3db39828f4f048

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Citations in the corpus

Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. (2012, background): “Their stable Foxp3 expression is ensured, at least partly, by an ‘‘epigenetic’’ mechanism, namely DNA demethylation of one of the conserved noncoding regions in the Foxp3 gene, termed Treg cell-specific demethylation region or TSDR (Floess et al., 2007; Huehn et al., 2009; Polansky et al., 2008; Zhe”
TGF-β Activation and Function in Immunity (2013, background): “In the setting of TCR engagement, Smad3 interacts with an enhancer region of the Foxp3 gene called CNS1 (62, 63).”
Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. (2011, positive): “(CNS2) in the Foxp3 gene represents a site for positive transcriptional autoregulation of Foxp3, providing a mechanism for the protein to maintain its own expression levels (Zheng et al., 2010).”
Regulatory T Cells and Foxp3 (2011, background): “One of these elements, CNS3, contains a DNase I hypersensitive site and is enriched in histone H3 monomethylated at position K4 (H3K4me1, a mark associated with enhancer elements) not only in Foxp3 expressing Treg cells, but also in their Foxp3negative thymic and peripheral precursors (50).”
Development and maintenance of regulatory T cells. (2013, background): “This region is also bound by Foxp3, Gata-3, and STAT5 in Treg cells, either directly or indirectly, and targeted deletion of the Foxp3 CNS2 region or Gata3 in Treg cells results in reduced transcription activity of Foxp3 (Rudra et al., 2012; Yao et al., 2007; Zheng et al., 2010).”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, background): “This binding, conditional upon demethylation of a CpG island within CNS2, affords heritable maintenance of the active state of the Foxp3 locus in the progeny of dividing Treg cells likely via yet-to-be-understood epigenetic mechanisms (65, 80).”
Peripheral CD4 T cell differentiation regulated by networks of cytokines and transcription factors (2010, background): “Our unpublished data suggest GATA3 also binds to Foxp3 CNS2; GATA3 deficiency in Tregs results in an unstable phenotype.”
Interleukin-2 at the Crossroads of Effector Responses, Tolerance, and Immunotherapy (2013, positive): “TCR-induced CpG hypomethylation of conserved noncoding DNA sequences (CNSs) critically regulates FOXP3 expression and is important for establishing Treg cell identity (Kim and Leonard, 2007; Ohkura et al., 2012; Zheng et al., 2010).”