Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA174179 | ENA |
REPOSITORIES: ENA
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Project description:Investigation of transcript level modulation in unstimulated and TGF-beta treated (with or without superimposed T-cell receptor and CD28 stimulation) naive CD4 T cells from wild type or Smad3-deficient littermate mice. Smad3 is a critical signaling molecule and transcription factor downstream of TGF-beta and mediates several of the TGF-beta dependent tolerogenic effects in T cells. This study was undertaken to unveil the transcriptionnal program controled by the TGF-b/Smad3 axis. Microarray study using RNA recovered after 6 hours of culture in either serum free media, serum-free media + TGF-beta (2.5ng/ml) or serum-free media + TGF-beta and anti-CD3e and anti-CD28 stimulation (3 conditions). Naive CD4 T cells (TCRb+, CD4+, CD62L+ and CD44-) were sorted from either wild type or Smad3 deficient littermates and submitted to the 3 culture conditions. Three biological replicates were obtained (each from at least 2 different mice). Thus a total of 18 Nimblegen 365K chip were used.
2012-08-31 | E-GEOD-40494 | biostudies-arrayexpress
Project description:Investigation of transcript level modulation in unstimulated and TGF-beta treated (with or without superimposed T-cell receptor and CD28 stimulation) naive CD4 T cells from wild type or Smad3-deficient littermate mice. Smad3 is a critical signaling molecule and transcription factor downstream of TGF-beta and mediates several of the TGF-beta dependent tolerogenic effects in T cells. This study was undertaken to unveil the transcriptionnal program controled by the TGF-b/Smad3 axis.
2012-08-31 | GSE40494 | GEO
Project description:TGF-b is an important pleiotropic cytokine with potent immunoregulatory properties. Although many previous reports have been proposed for the immunoregulatory functions of TGF-b on T cells, such as the suppression of cell proliferation, cytokine production and cytokine signaling, as well as the induction of apoptosis, it is not well elucidated whether the each effect of TGF-b on T cells is dependent on Smad signaling or Smad-independent other signaling pathways. The aim of the study was to clarify the involvement of Smad signaling and to investigate the redundancy of Smad2 and Smad3 on various TGF-b-mediated regulation of gene expression in CD4+ T cells. We used microarrays to detail the global program of gene expression regulated by TGF-b in CD4+ T cells, and identified distinct classes of up/down-regulated genes which are dependent on or independent of TGF-b-Smad signaling. Most of genes regulated by TGF-b were redundantly dependent on Smad2 and Smad3, including Foxp3 and IL-2. In addition, some genes were sufficiently regulated via Smad2 or Smad3 signaling alone. In contrast, TGF-b-mediated RORgt induction was independent of Smad signaling. CD4+CD25-CD44loCD62Lhi T cells (naive) were isolated from the spleens in wild-type (WT), T cell-specific Smad2 conditional knockout (Smad2KO or Smad2del/del), Smad3 knockout (Smad3KO or Smad3-/-) or Smad2del/delSmad3+/- mice by using a BD FACS ariaTM cell sorter (BD Bioscience) (purity: >98%). Freshly purified cells were then stimulated with anti-TCR stimuli in the absence or presence of TGF-b for 24 hr, respectively. A complete and precise experimental procedure is given in the "treatment protocol". It was very difficult to obtain the enough number of CD4+CD25-CD44loCD62Lhi naive T cells from Smad2del/delSmad3-/- mice because alomost all of CD4+ T cells were activated in Smad2del/delSmad3-/- mice. We confirmed that the several known Smad-regulated genes were almost out of control in Smad2del/delSmad3+/- CD4+ T cells by using quantitative RT-PCR. Furthermore, previous studies have reported the similar results in other cell types deficit in two alleles of Smad2 and one allele of Smad3. For these reasons, we substituted Smad2del/delSmad3+/- naive T cells for Smad2/3-deficient naive T cells. Cells were quickly collected 24 hr after culture for RNA extraction and hybridization on Affymetrix microarrays.
2010-07-29 | E-GEOD-19601 | biostudies-arrayexpress
Project description:Transforming growth factor-beta (TGF-beta) transmits signals that facilitate cancer progression. Especially, epithelial-mesenchymal transition (EMT) induced by TGF-beta is considered to crucially contribute to the malignant phenotype of cancer cells. Here we report that the EMT-associated cellular responses induced by TGF-beta are mediated through distinct signaling pathways that diverge at Smad3; cell motility and epithelial marker downregulation are Smad3-dependent while mesenchymal marker induction is not. Furthermore, using a chimeric protein approach in SMAD3 knockout A549 cells, we found that the beta 4 region in the MH1 domain of Smad3 is indispensable for TGF-beta–induced cell motility, but not for epithelial marker downregulation. A transcriptome analysis was performed using A549 cells expressing Smad3 mutant of the MH1 domain.
2021-03-10 | GSE152015 | GEO
Project description:CD4(+)Foxp3(+) regulatory T (Treg) cells originate primarily from thymic differentiation, but conversion of mature T lymphocytes to Foxp3 positivity can be elicited by several means, including in vitro activation in the presence of TGF-beta. Retinoic acid (RA) increases TGF-beta-induced expression of Foxp3, through unknown molecular mechanisms. We showed here that, rather than enhancing TGF-beta signaling directly in naive CD4(+) T cells, RA negatively regulated an accompanying population of CD4(+) T cells with a CD44(hi) memory and effector phenotype. These memory cells actively inhibited the TGF-beta-induced conversion of naive CD4(+) T cells through the synthesis of a set of cytokines (IL-4, IL-21, IFN-gamma) whose expression was coordinately curtailed by RA. This indirect effect was evident in vivo and required the expression of the RA receptor alpha. Thus, cytokine-producing CD44(hi) cells actively restrain TGF-beta-mediated Foxp3 expression in naive T cells, and this balance can be shifted or fine-tuned by RA. All gene expression profiles were obtained from highly purified T cell populations sorted by flow cytometry. To reduce variability, cells from multiple mice were pooled for sorting, and replicates were generated for essentially all groups. RNA from 0.5-3 x 105 cells was amplified, labeled, and hybridized to Affymetrix M430v2 microarrays. Raw data were preprocessed with the RMA algorithm in GenePattern, and averaged expression values were used for analysis.
2008-11-16 | E-GEOD-13306 | biostudies-arrayexpress
Project description:Cellular binary fate decisions require the progeny to silence genes associated with the alternative fate. The major subsets of alpha:beta T cells have been extensively studied as a model system for fate decisions. While the transcription factor RUNX3 is required for the initiation of Cd4 silencing in CD8 T cell progenitors, it is not required to maintain the silencing of Cd4 and other helper T lineage genes. The other runt domain containing protein, RUNX1, silences Cd4 in an earlier T cell progenitor, but this silencing is reversed whereas the gene silencing after RUNX3 expression is not reverse. Therefore, we hypothesized that RUNX3 and not RUNX1 recruits other factors that maintains the silencing of helper T lineage genes in CD8 T cells. To this end, we performed a proteomics screen of RUNX1 and RUNX3 to determine candidate silencing factors.
2019-11-12 | PXD007511 | Pride
Project description:CD4(+)Foxp3(+) regulatory T (Treg) cells originate primarily from thymic differentiation, but conversion of mature T lymphocytes to Foxp3 positivity can be elicited by several means, including in vitro activation in the presence of TGF-beta. Retinoic acid (RA) increases TGF-beta-induced expression of Foxp3, through unknown molecular mechanisms. We showed here that, rather than enhancing TGF-beta signaling directly in naive CD4(+) T cells, RA negatively regulated an accompanying population of CD4(+) T cells with a CD44(hi) memory and effector phenotype. These memory cells actively inhibited the TGF-beta-induced conversion of naive CD4(+) T cells through the synthesis of a set of cytokines (IL-4, IL-21, IFN-gamma) whose expression was coordinately curtailed by RA. This indirect effect was evident in vivo and required the expression of the RA receptor alpha. Thus, cytokine-producing CD44(hi) cells actively restrain TGF-beta-mediated Foxp3 expression in naive T cells, and this balance can be shifted or fine-tuned by RA.
2008-11-16 | GSE13306 | GEO
Project description:TGF-betas have complex roles in tumorigenesis, with context-dependent effects that can either suppress or promote tumor progression. Our goal was to use integrated genomic approaches in a model of human breast cancer progression to identify core TGF-beta-regulated genes that specifically reflect the tumor suppressor activity of TGF-beta. The model consisted of the non-tumorigenic MCF10A (“M1”), the premalignant MCF10AT1k.cl2 (“M2”), the early malignant MCF10Ca1h (“M3”) and the highly malignant, metastatic MCF10Ca1a.cl1 (“M4”) cell lines. We have previously shown that tumor suppressor activity of TGF-beta is dependent on Smad3, and is lost in M4 cells. To identify how TGF-beta/Smad3 targets change with cancer progression, we performed promoter-wide Smad3 ChIP-chip on all four cell lines of the breast cancer progression model (M1-M4), following treatment with TGF-beta or vehicle control.
2015-01-01 | GSE34271 | GEO
Project description:Mitogen-activated protein kinases (MAPKs) are key mediators of the T cell receptor (TCR) signals but their roles in T helper (Th) cell differentiation are unclear. Here we showed that the MAPK kinase kinases MEKK2 (encoded by Map3k2) and MEKK3 (encoded by Map3k3),negatively regulated transforming growth factor-beta (TGF-beta)-mediated Th cell differentiation.Map3k2-/-Map3k3Lck-Cre/- mice showed an abnormal accumulation of regulatory T (Treg) and Th17 cells in the periphery, consistent with Map3k2-/-Map3k3Lck-Cre/- naïve CD4+ T cells’ differentiation into Treg and Th17 cells with a higher frequency than wild-type (WT) cells after TGF-beta stimulation in vitro. In addition, Map3k2-/-Map3k3Lck-Cre/- mice developed more severe experimental autoimmune encephalomyelitis. Map3k2-/-Map3k3Lck-Cre/- T cells exhibited impaired phosphorylation of the SMAD2 and SMAD3 proteins at their linker regions, which negatively regulated the TGF-beta responses in T cells. Thus, the crosstalk between TCR-induced MAPK and the TGF-beta signaling pathways is important in regulating Th cell differentiation. CD4+CD62L-CD44+ cells were FACS sorted from C57BL/6 Lck-Cre MEKK2 KO MEKK3F/-(dKO) or C57BL/6 WT mice
2011-02-02 | E-GEOD-26987 | biostudies-arrayexpress
Project description:Transforming growth factor (TGF)-beta induces apoptosis of many types of cancer cells and acts as a tumor suppressor. We found lower expression of TGF-beta type II receptor (TbRII) in most of SCLC cells and tissues than in normal lung epithelial cells and normal lung tissues, respectively. In vitro cell growth and in vivo tumor formation were suppressed by TGF-beta-mediated apoptosis when the wild-type TbRII was overexpressed in SCLC cells. We therefore determined Smad2 and Smad3 (Smad2/3) binding sites in a SCLC cell line H345 stably expressing exogenous TbRII (H345-TbRII) to identify target genes of TGF-beta. Smad2 and Smad3 binding sites in H345-TbRII cells were determined by ChIP-seq (one sample analysis, without replicates).
2015-09-15 | E-GEOD-63871 | biostudies-arrayexpress