Dataset Information

TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3.

ABSTRACT: Expression of FOXP3, a potent gene-specific transcriptional repressor, in regulatory T cells is required to suppress autoreactive and alloreactive effector T cell function. Recent studies have shown that FOXP3 is an acetylated protein in a large nuclear complex and FOXP3 actively represses transcription by recruiting enzymatic corepressors, including histone modification enzymes. The mechanism by which extracellular stimuli regulate the FOXP3 complex ensemble is currently unknown. Although TGF-beta is known to induce murine FOXP3(+) Treg cells, TGF-beta in combination with IL-6 attenuates the induction of FOXP3 functional activities. Here we show that TCR stimuli and TGF-beta signals modulate the disposition of FOXP3 into different subnuclear compartments, leading to enhanced chromatin binding in human CD4(+)CD25(+) regulatory T cells. TGF-beta treatment increases the level of acetylated FOXP3 on chromatin and site-specific recruitment of FOXP3 on the human IL-2 promoter. However, the proinflammatory cytokine IL-6 down-regulates FOXP3 binding to chromatin in the presence of TGF-beta. Moreover, histone deacetylation inhibitor (HDACi) treatment abrogates the down-regulating effects of IL-6 and TGF-beta. These studies indicate that HDACi can enhance regulatory T cell function via promoting FOXP3 binding to chromatin even in a proinflammatory cellular microenvironment. Collectively, our data provide a framework of how different signals affect intranuclear redistribution, posttranslational modifications, and chromatin binding patterns of FOXP3.

SUBMITTER: Samanta A

PROVIDER: S-EPMC2544572 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3.

Samanta Arabinda A Li Bin B Song Xiaomin X Bembas Kathryn K Zhang Geng G Katsumata Makoto M Saouaf Sandra J SJ Wang Qiang Q Hancock Wayne W WW Shen Yuan Y Greene Mark I MI

Proceedings of the National Academy of Sciences of the United States of America 20080908 37

Expression of FOXP3, a potent gene-specific transcriptional repressor, in regulatory T cells is required to suppress autoreactive and alloreactive effector T cell function. Recent studies have shown that FOXP3 is an acetylated protein in a large nuclear complex and FOXP3 actively represses transcription by recruiting enzymatic corepressors, including histone modification enzymes. The mechanism by which extracellular stimuli regulate the FOXP3 complex ensemble is currently unknown. Although TGF-b ...[more]

PMID: 18779564

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Project description:Background: Inflammatory bowel disease (IBD) involves an increase in T effector cells in the intestines that disrupts the normal balance with T regulatory cells (Tregs). A therapy that restores this balance has the potential to treat IBD. We have shown that epicutaneous exposure to OVA induces Tregs that are able to induce tolerance. The Tregs also migrate to the intestines where they alleviate colitis in mice, demonstrating the potential for skin induced Tregs to treat intestinal inflammation. We investigated the role of Foxp3, IL-10, and TGF-β in the suppression of colitis by epicutaneous immunotherapy (ET). Methods: RAG1-/- mice were transferred with CD4+CD45RBhi T cells from wild type mice to induce colitis. To determine whether Foxp3+ Tregs, IL-10-, or TGF-β-producing Tregs were necessary, Foxp3-DTR, IL-10-/-, or CD4-dnTGFBRII mice were immunized with OVA and OVA TCR enriched T cells were added. As control groups, some mice were given OVA TCR enriched T cells from wild type mice or no OVA TCR enriched T cells. Half of the mice in each group were then exposed on the skin to Viaskin patches containing OVA weekly for 3 weeks. Mice given OVA TCR enriched T cells from Foxp3-DTR mice were given diphtheria toxin (DT) or not in addition to ET. Mice were assessed for weight loss, colon length, colonic cytokine production, and histological inflammation. Results: ET, after injection with OVA TCR enriched T cells derived from wild type mice, prevented weight loss, decreased colonic inflammatory cytokine production and histological colitis. ET in the absence of the OVA TCR enriched T cells did not alleviate colitis. ET, after injection with OVA TCR enriched T cells derived from Foxp3-DTR mice, prevented weight loss, decreased colonic inflammatory cytokine production, and histological colitis. Ablation with DT did not impair the ability of ET to alleviate colitis. ET failed to alleviate colitis when OVA TCR enriched T cells were derived from IL-10-/- or CD4-dnTGFBRII mice. Conclusions: ET through induction of Tregs, which produce IL-10 and TGF-β, could be a promising treatment for IBD.

Dataset Information

TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3.

Publications

TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3.

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