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Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation.

ABSTRACT: Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T(eff) cell) function and gain of suppressive activity by T(reg) cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T(reg) cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3' untranslated region. Release of SATB1 from the control of Foxp3 in T(reg) cells caused loss of suppressive function, establishment of transcriptional T(eff) cell programs and induction of T(eff) cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T(reg) cell functionality.

SUBMITTER: Beyer M

PROVIDER: S-EPMC3669688 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation.

Beyer Marc M Thabet Yasser Y Müller Roman-Ulrich RU Sadlon Timothy T Classen Sabine S Lahl Katharina K Basu Samik S Zhou Xuyu X Bailey-Bucktrout Samantha L SL Krebs Wolfgang W Schönfeld Eva A EA Böttcher Jan J Golovina Tatiana T Mayer Christian T CT Hofmann Andrea A Sommer Daniel D Debey-Pascher Svenja S Endl Elmar E Limmer Andreas A Hippen Keli L KL Blazar Bruce R BR Balderas Robert R Quast Thomas T Waha Andreas A Mayer Günter G Famulok Michael M Knolle Percy A PA Wickenhauser Claudia C Kolanus Waldemar W Schermer Bernhard B Bluestone Jeffrey A JA Barry Simon C SC Sparwasser Tim T Riley James L JL Schultze Joachim L JL

Nature immunology 20110814 9

Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T(eff) cell) function and gain of suppressive activity by T(reg) cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T(reg) cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB ...[more]

PMID: 21841785

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Project description:Regulatory T (Treg) cells are involved in self tolerance, immune homeostasis, prevention of autoimmunity, and suppression of immunity to pathogens or tumours. The forkhead transcription factor FOXP3 is essential for Treg cell development and function as mutations in FOXP3 cause severe autoimmunity in mice and humans. However, the FOXP3-dependent molecular mechanisms leading to this severe phenotype are not well understood. Here we introduce the chromatin remodelling enzyme SATB1 (special AT-rich sequence-binding protein-1) as an important target gene of FOXP3. So far, SATB1 has been associated with normal thymic T-cell development, peripheral T-cell homeostasis, TH1/TH2 polarization, and reprogramming of gene expression. In natural and induced murine and human FOXP3+ Treg cells SATB1 expression is significantly reduced. While there is no differential epigenetic regulation of the SATB1 locus between Treg and Teffector cells, FOXP3 reduces SATB1 expression directly as a transcriptional repressor at the SATB1 locus and indirectly via miR-155 induction, which specifically binds to the 3’UTR of the SATB1 mRNA. Reduced SATB1 expression in FOXP3+ cells achieved either by overexpression or induction of FOXP3 is linked to significant reduction in TH1 and TH2 cytokines, while loss of FOXP3 function either by knock down or genetic mutation leads to significant upregulation of SATB1 and subsequent cytokine production. Alltogether, these findings demonstrate that reduced SATB1 expression in Treg cells is necessary for maintenance of a Treg-cell phenotype in vitro and in vivo and places SATB1-mediated T cell-specific modulation of global chromatin remodelling central during the decision process between effector and regulatory T-cell function. Gene expression profiling of freshly isolated CD4+ T cells, separated into CD25 negative and positive subpopulations, from three different donors. FOXP3 is stably and constitutively expressed at a high level in CD4+CD25+ regulatory T cells and at a low level in CD4+CD25- cells.

Dataset Information

Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation.

Publications

Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation.

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