Unknown,Transcriptomics,Genomics,Proteomics

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The dependence on NFAT levels discriminates conventional T cells from Foxp3 expressing regulatory cells

ABSTRACT: In this study, we used microarrays to investigate the gene expression program in conventional T cells, nTreg and conventional T cells treated with TGFbeta (iTreg) from wild-type mice and and mice having NFAT1/NFAT2 double-deficient (DKO) T cells. CD4+CD25- and CD4+CD25+ T cells were isolated by MACS and stimulated for 24 h with anti-CD3 and anti-CD28 antibodies in the absence or presence of TGFbeta. RNA was extracted and microarray analyses were performed. The data represents two independent biological replicates.

ORGANISM(S): Mus musculus

SUBMITTER: Gerd Mueller

PROVIDER: E-MEXP-3687 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Vaeth Martin M Schliesser Ulrike U Müller Gerd G Reissig Sonja S Satoh Kazuki K Tuettenberg Andrea A Jonuleit Helmut H Waisman Ari A Müller Martin R MR Serfling Edgar E Sawitzki Birgit S BS Berberich-Siebelt Friederike F

Proceedings of the National Academy of Sciences of the United States of America 20120918 40

Several lines of evidence suggest nuclear factor of activated T-cells (NFAT) to control regulatory T cells: thymus-derived naturally occurring regulatory T cells (nTreg) depend on calcium signals, the Foxp3 gene harbors several NFAT binding sites, and the Foxp3 (Fork head box P3) protein interacts with NFAT. Therefore, we investigated the impact of NFAT on Foxp3 expression. Indeed, the generation of peripherally induced Treg (iTreg) by TGF-β was highly dependent on NFAT expression because the ab ...[more]

PMID: 22991461

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Project description:The epigenetic regulation of transcription factor genes is critical for T cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and required for stable expression of FOXP3 and suppressive function. We analyzed the impact of hypomethylating agents 5-Aza-2`-deoxycytidine and Epigallocatechin-3-gallate (EGCG) on human CD4+CD25- T for generating Treg cell specific DNA methylation pattern within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage specifying transcription factors of the major T cell lineages and their leading cytokines, functional properties and global transcriptome changes were analyzed. 5-Aza-2`-deoxycytidine induced FOXP3-TSDR methylation and expression of Treg cell specific genes FOXP3 and LRRC32. Proliferation of 5-Aza-2Â´deoxycytidine treated cells was reduced, but they did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of Th1 and Th17 cells were induced. EGCG induced global DNA hypomethylation to a lower degree than 5-Aza-2Â´deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg cell specific genes. Both DNMT inhibitors did not induce full functional human Treg cells. Although 5-Aza-2`-deoxycytidine treated cells phenotypically appeared to be Treg cells, they did not suppress proliferation of responder cells, which is an essential capability to be used in Treg cell transfer therapy. In this study we analyze the potency of the two hypomethylating agents 5-Aza-2`-deoxycytidine (5-Aza-dC) and Epigallocatechin-3-gallate (EGCG) for in vitro induction of functional Treg cell cells through generation of a specific methylation pattern within FOXP3-TSDR. We analyzed the expression of Treg cell specific genes and for their functional properties from CD4+CD25- T cells. 5-Aza-dC is a derivative of 5-Azacytidine. Both substances are inhibitors of DNA methyltransferases (DNMTs) and used for therapy of patients with myelodysplastic syndrome and acute myeloid leukaemia. In these patients, 5-Azacytidine has been reported to augment regulatory T cell expansion in blood. EGCG is the most abundant catechin of green tea and has been reported to have cardio protective, anti-cancer, anti-infective properties and protective effects on autoimmune diseases. EGCG has also been described as a potent inhibitor of DNMTs and to induce Foxp3 in Jurkat T cell line.

Dataset Information

The dependence on NFAT levels discriminates conventional T cells from Foxp3 expressing regulatory cells

Publications

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

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