Tonic Signaling Controls Gene Expression in T Lymphocytes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76897 | GEO | 2017/05/23
SECONDARY ACCESSION(S): PRJNA308898
REPOSITORIES: GEO
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Project description:Signal transduction pathways guided by cellular receptors commonly exhibit low-level constitutive signaling in a continuous, ligand-independent manner. The dynamic equilibrium of positive and negative regulators establishes such a tonic signal. Ligandindependent signaling by the precursors of mature antigen receptors regulates development of B- and T-lymphocytes. Here we describe a basal signal controlling gene expression profiles in the Jurkat T cell line and mouse thymocytes. Using DNA microarrays and Northern blots to analyze unstimulated cells, we demonstrate that expression of a cluster of genes, including RAG-1 and RAG2, is repressed by constitutive signals requiring the adapter molecules LAT and SLP-76. This TCR-like pathway results from constitutive low-level activity of Erk and Abl kinases. Inhibition of Abl by the drug STI-571 or events upstream of Erk increases RAG-1 expression. Our data suggest that physiologic gene expression programs depend upon tonic activity of signaling pathways independent of receptor ligation.
2005-10-14 | E-SMDB-2194 | biostudies-arrayexpress
Project description:Title of Publication: Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes Abstract of publicaton: CD4/CD8 double-positive (DP) thymocytes express the transcriptional repressor Histone Deacetylase 7 (HDAC7), a class IIa HDAC that is exported from the cell nucleus after T cell receptor (TCR) engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in thymocytes, and regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR J segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAP kinase activity that contributes to the observed loss of viability. Remarkably, the activity of Protein Kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining auto-excitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. Goal of Microarray experiment: We did these experiments to determine how alteration of the function of HDAC7, a site-specific and signal-dependent repressor of transcription, changes gene expression in CD4/CD8 DP thymocytes. Three biological replicate samples were prepared for each non-wild type mouse strain (Samples 7-18). Six biological replicates were prepared for the wild type strain (Samples 1-6). Total RNA was prepared from isolated CD4/CD8 Double-positive thymocytes and labeled with the Affymetrix Whole-Transcript labeling protocol. Labeled probes were hybridized to one Affymetrix Mouse Gene 1.0ST array each. Data from .cel files were normalized using RMA, in normalization groups representing each of the binary comparisons made. These binary comparisons between sample groups represent gene expression changes due to loss of HDAC7 (samples 1-3 vs. 7-9), transgenic expression of an HDAC7-VP16 fusion protein (samples 4-6 vs. 10-12), positive thymic selection (samples 1-6 vs. samples 11-15), and negative thymic selection (Samples 11-15 vs. samples 16-18).
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Project description:Naïve T cells constantly experience TCR signals in response to self-peptides presented by MHC (pMHC) in vivo. The intensity of these basal or tonic TCR signals can be indirectly read out by expression of surrogate markers of tonic TCR signaling, including the Nur77-GFP transgene and Ly6c. The strength of tonic TCR signaling varies broadly across the naïve CD4+ T cell population and is correlated with functional heterogeneity.Cells that experience the most basal TCR signaling (Nur77-GFP hi, Ly6c lo) are hyporesponsive to peptide-MHC stimulation. Here we examine whether tonic TCR stimulation is associated with differences in mRNA expression.
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Project description:Naïve T cells constantly experience TCR signals in response to self-peptides presented by MHC (pMHC) in vivo. The intensity of these basal or tonic TCR signals can be indirectly read out by expression of surrogate markers of tonic TCR signaling, including the Nur77-GFP transgene and Ly6c. The strength of tonic TCR signaling varies broadly across the naïve CD4+ T cell population and is correlated with functional heterogeneity.Cells that experience the most basal TCR signaling (Nur77-GFP hi, Ly6c lo) are hyporesponsive to peptide-MHC stimulation. Here we examine whether tonic TCR stimulation is associated with differences in chromatin accessibility.
2022-08-22 | GSE206072 | GEO
Project description:Signal transduction pathways guided by cellular receptors commonly exhibit low-level constitutive signaling in a continuous, ligand-independent manner. The dynamic equilibrium of positive and negative regulators establishes such a tonic signal. Ligandindependent signaling by the precursors of mature antigen receptors regulates development of B- and T-lymphocytes. Here we describe a basal signal controlling gene expression profiles in the Jurkat T cell line and mouse thymocytes. Using DNA microarrays and Northern blots to analyze unstimulated cells, we demonstrate that expression of a cluster of genes, including RAG-1 and RAG2, is repressed by constitutive signals requiring the adapter molecules LAT and SLP-76. This TCR-like pathway results from constitutive low-level activity of Erk and Abl kinases. Inhibition of Abl by the drug STI-571 or events upstream of Erk increases RAG-1 expression. Our data suggest that physiologic gene expression programs depend upon tonic activity of signaling pathways independent of receptor ligation. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2005-12-29 | GSE3922 | GEO
Project description:The aim of the dataset was to study on a genome-wide level the impact of Lat deficiency on gene expression in resting and activated CD4+ T cells Lat+ and Lat? CD4+ T cells were isolated from lymph nodes and spleen of Latfl-dtr Tmat-Cre mice using a Dynabeads untouched mouse CD4 cells kit (Life Technology) and further purified by cell sorting. Lat+ CD4+ T cells were defined as: CD5+, hDTR+, CD8?, TCR???, CD25?, CD69?, CD62L+, lineage (CD11c, CD11b, CD19, CD45R, CD161)? and Lat? CD4+ Tcells were defined as: CD5+, hDTR?, CD8?, TCR???, CD25?, CD69?, CD62L+, lineage (CD11c, CD11b, CD19, CD45R, CD161)?. Sorted Lat+ or Lat? CD4+ T cells were then kept in vitro for 4 hours without stimulation or activated for 4 hours using anti-CD3 antibody and anti-CD28 antibody. Cell samples corresponding to three biological replicates were analyzed and gene expression profiles were obtained from total RNA.
2014-03-02 | E-GEOD-49507 | biostudies-arrayexpress
Project description:We profiled the transcriptomes of 4 human lung cell types that were subjected to control (non-stretch) and 30% tonic stretch conditions for 4 hours and 24 hours.
2016-04-12 | GSE80161 | GEO
Project description:We profiled the transcriptomes of 4 human lung cell types that were subjected to control (non-stretch) and 30% tonic stretch conditions for 4 hours and 24 hours. Total RNA extracted from cells under control (time-matched) or 30% stretch conditions (4 hours or 24 hours) performed in technical replicate experiments. human lung alveolar A549 cells, human lung bronchoepithelial 16HBE14o- cells, human fetal lung fibroblasts CCL-153, human juvenile lung fibroblasts CCL-151
2016-04-12 | E-GEOD-80161 | biostudies-arrayexpress
Project description:The existence of immunoregulatory mechanisms that control autoimmunity in non-lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we found that psoriasis is tightly associated with a significant downregulation of fatty acid metabolism and biosynthesis pathways as well as Th2 signature genes. Among lipids-activated transcription factors, LXR and PPAR were required for fatty acid homeostasis and resistance to psoriasis in mice. STAT6 played a role in the homeostatic expression of LXR and PPARγ in the skin. Additionally, innate lymphoid cells established tonic type 2 immunity in normal skin by producing IL-13 continually. Mice lacking tonic type 2 immunity were more susceptible to psoriatic inflammation in vivo. In human skin, inhibiting tonic type 2 immunity worsened psoriasis-like inflammation and IL-17 production, while activating LXR or PPAR inhibited them. Therefore, tonic type 2 immunity is an essential tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.
2024-04-08 | GSE229198 | GEO
Project description:Abstract of publicaton: CD4/CD8 double-positive (DP) thymocytes express the transcriptional repressor Histone Deacetylase 7 (HDAC7), a class IIa HDAC that is exported from the cell nucleus after T cell receptor (TCR) engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in thymocytes, and regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR Jalpha segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAP kinase activity that contributes to the observed loss of viability. Remarkably, the activity of Protein Kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining auto-excitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. Title of manuscript: Nuclear Export of Histone Deacetylase 7 During Thymic Selection Mediates Immune Self-tolerance. abstract of manuscript: Histone Deacetylase 7 (HDAC7) is a TCR signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-?P) in thymocytes. We find that HDAC7-?P Transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression program in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. Goal of Microarray experiment: We did these experiments to determine how alteration of the function of HDAC7, a site-specific and signal-dependent repressor of transcription, changes gene expression in CD4/CD8 DP thymocytes.
2011-04-06 | GSE26488 | GEO