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Transcriptome analysis of Foxp3- CD25- regulatory T cells

ABSTRACT: The concept of immune regulation/suppression has been well-established. With thymus-derived CD4 CD25 regulatory T (TR) cells, it became clear that a variety of additional peripherally induced TR cells play vital roles in protection from many harmful immune responses including intestinal inflammation. In the present study, we have analyzed in vivo-induced Ag-specific CD4 TR cells with respect to their molecular and functional phenotype. By comparative genomics we could show that these Ag-specific TR cells induced by chronic Ag stimulation in vivo clearly differ in their genetic program from naturally occurring thymus-derived CD4 CD25 TR cells. This distinct population of induced TR cells express neither CD25 nor the TR-associated transcription factor Foxp3. Strikingly, CD25 is not even up-regulated upon stimulation. Despite the lack in Foxp3 expression, these in vivo-induced CD25 TR cells are able to interfere with an Ag-specific CD8 T cell-mediated intestinal inflammation without significant increase in CD25 and Foxp3 expression. Thus, our results demonstrate that in vivo-induced Ag-specific TR cells represent a distinct population of Foxp3 CD25 TR cells with regulatory capacity both in vitro and in vivo. Keywords: cell type comparison

ORGANISM(S): Mus musculus

PROVIDER: GSE12506 | GEO | 2008/08/21

SECONDARY ACCESSION(S): PRJNA113255

REPOSITORIES: GEO

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Project description:Naturally occurring CD25+CD4+ regulatory T cells (T reg cells) are currently intensively characterized because of their major importance in modulating host responses to tumors and infections, in preventing transplant rejection, and in inhibiting the development of autoimmunity and allergy. Originally, CD4+ T reg cells were identified exclusively by the constitutive expression of CD25, and many in vivo experiments have been performed using depleting antibodies directed against CD25. However, both the existence of CD25– T reg cells, especially within peripheral tissues, as well as the expression of CD25 on activated conventional T cells, which precludes discrimination between T reg cells and activated conventional T cells, limits the interpretation of data obtained by the use of anti-CD25 depleting antibodies. The most specific T reg cell marker currently known is the forkhead box transcription factor Foxp3, which has been shown to be expressed specifically in mouse CD4+ T reg cells and acts as a master switch in the regulation of their development and function. To address the question of the in vivo role of T reg cells in immunopathology, we have generated bacterial artificial chromosome (BAC)–transgenic mice termed depletion of regulatory T cell (DEREG) mice, which express a diphtheria toxin receptor (DTR) enhanced GFP (eGFP) fusion protein under the control of the foxp3 locus, allowing both detection and inducible depletion of Foxp3+ T reg cells. The gene expression profile of both CD4+eGFP+FoxP3+ and CD4+eGFPnegFoxP3neg cells isolated from DEREG mice was here analyzed by micro array. Keywords: DEREG, FoxP3, FoxP3-EGFP, mouse, regulatory T cell, CD4 CD4+GFP+FoxP3+ and CD4+GFPnegFoxP3neg cells were isolated from DEREG mice by negative selection of CD4+ T cells (Invitrogen Kit) and subsequent FACS sorting for GFP+ and GFPneg cells. Purity was greater than 99 %. cRNA was prepared according to the Affymetrix Labeling Protocol, fragmented and hybridized to Affymetrix GeneChip Mouse Genome 430.

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.

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Transcriptome analysis of Foxp3- CD25- regulatory T cells

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