CREB/ATF-dependent T cell receptor–induced FoxP3 gene expression: a role for DNA methylation

By Hyoung-Pyo Kim, W. Leonard. Journal of Experimental Medicine, 2007

639 citations recorded by the source corpus.

Regulatory T cells (T reg cells) are a population of CD4+ T cells that limit immune responses. FoxP3 is a master control transcription factor for development and function of these cells, but its regulation is poorly understood. We have identified a T cell receptor–responsive enhancer in the FoxP3 first intron that is dependent on a cyclic-AMP response element binding protein (CREB)/activating transcription factor (ATF) site overlapping a CpG island. Methylation of this island inversely correlates with CREB binding and FoxP3 expression. Interestingly, transforming growth factor-β, which induces T reg cell formation, decreases methylation of the CpG island and increases FoxP3 expression. Similarly, inhibiting methylation with 5-azacytidine or knocking down the DNA methyltransferase Dnmt1 also induces FoxP3 expression. Conversely, methylation of the CpG island, which decreases CREB binding or expression of dominant-negative CREB, decreases FoxP3 gene expression. Thus, T cell receptor–induced FoxP3 expression in T reg cells is controlled both by sequence-specific binding of CREB/ATF and by DNA methylation of a CpG island.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/89799d393321a3f7d9175639aac9493ce5e8933a

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Citations in the corpus

Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. (2009, background): “Previous work has demonstrated DNA demethylation, H3K4me3 modification, and H3 acetylation in the Foxp3 promoter in CD25+ nTreg cells (Floess et al., 2007; Kim and Leonard, 2007).”
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).”
Control of regulatory T cell lineage commitment and maintenance (2009, background): “In addition, CREB-ATF-1 was shown to bind an intronic regulatory region at the Foxp3 locus (Foxp3 conserved noncoding sequence 2, Foxp3-CNS2) and enhance expression of a luciferase reporter driven by a Foxp3 promoter in a transient transfection assay (Kim and Leonard, 2007).”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, background): “In agreement with this hypothesis, knockdown, pharmacologic inhibition, or ablation of the Dnmt1 gene and resultant CpG motif demethylation increases both the induction and, critically, the stability of Foxp3 expression (62, 65, 70).”
T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR (2008, positive): “Inter-estingly, H3K4 di-and trimethylation was found near the Foxp3 TSS (34) and the 5 (cid:1) UTR not only in Foxp3 (cid:2) cells but also in 18-h activated CD4 T cells, which had the potential for Foxp3 induction but did not actually express Foxp3.”
Foxp3 instability leads to the generation of pathogenic memory T cells in vivo (2009, positive): “To directly address the stability of the Foxp3 locus in this newly identified population, we examined the methylation status of the T reg cell–specific demethylated region (TSDR) of Foxp3 in various T cell subset”
Plasticity of CD4+ T cell lineage differentiation. (2009, background): “Besides the promoter and an intronic enhancer, a highly conserved CpGrich element is present upstream of exon 1 in the Foxp3 locus and is referred to as the Treg cell-specific demethylated region (TSDR) (Floess et al., 2007; Kim and Leonard, 2007; Baron et al., 2007; Nagar et al., 2008).”
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).”
T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. (2012, background): “CREB/ATF was also shown to bind to the CNS2 region in a demethylation-dependent manner (Kim and Leonard, 2007).”