The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE72408 | GEO | 2015/09/15
REPOSITORIES: GEO
Similar Datasets
Project description:T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during infection. We find that at high concentrations T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential. Splenocyte derived CD8+ T cells from C57BL/6 mice with either a wildtype (WT) (GzmB-Cre Zeb2+/+) or GzmB-Cre Zeb2-fl/fl (Zeb2-/-) backgrounds, following 8 days post infection with LCMV-Armstrong, were subsetted into KLRG1-hi/IL-7R-lo populations (terminal effectors, TE) or KLRG1-lo/IL-7R-hi (memory precursors, MP) populations. Four experimental groups, each with 3 samples, comprised of TE+WT, MP+WT, TE+ZEB2-/-, and MP+ZEB2-/-, were profiled for gene expression utilizing a polyA RNA prep and hybridized to the Illumina microarray platform IlluminaWG-v2.0.
2015-09-15 | E-GEOD-72408 | biostudies-arrayexpress
Project description:ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in EMT-dependent tumor metastasis. While the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is upregulated by activated T cells, specifically in the KLRG1hi effector CD8+ T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8+ T cells following primary and secondary infection with a severe impairment in the generation of the KLRG1hi effector-memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress CD127 and IL-2 in CD8+ T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box-sites in the ZEB2 gene and that T-bet and ZEB2 regulate similar gene-expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Taken together, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8+ T cells. Zeb2WT, Zeb2KO, T-betWT and T-betKO effector CD8+ T cells were sorted into Trizol at day 6 of infection. Two or more replicates per sample were analyzed
2015-09-19 | E-GEOD-72162 | biostudies-arrayexpress
Project description:T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 controls de novo access to memory CTL-specific cistromes prior to the first cell division, and is essential for memory CTL differentiation. Runx3 specifically promotes accessibility of cis-acting regions highly enriched with IRF, bZIP and Prdm1-like family TF motifs, upregulates IRF4 and establishes feed-forward transcriptional circuits that induce fundamental CTL attributes in memory precursor cells. Runx3 drives uncoupling from the naïve cell state, but subsequently restrains terminal differentiation of nascent CTL by preventing high expression of the TF T-bet and slowing effector cell proliferation. Enforced Runx3 expression enhances memory CTL differentiation and increases their numbers during iterative infections. Thus, Runx3 functions in a pioneering role to initialize and then ensure memory CTL differentiate.
2018-04-19 | GSE111144 | GEO
Project description:T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 controls de novo access to memory CTL-specific cistromes prior to the first cell division, and is essential for memory CTL differentiation. Runx3 specifically promotes accessibility of cis-acting regions highly enriched with IRF, bZIP and Prdm1-like family TF motifs, upregulates IRF4 and establishes feed-forward transcriptional circuits that induce fundamental CTL attributes in memory precursor cells. Runx3 drives uncoupling from the naïve cell state, but subsequently restrains terminal differentiation of nascent CTL by preventing high expression of the TF T-bet and slowing effector cell proliferation. Enforced Runx3 expression enhances memory CTL differentiation and increases their numbers during iterative infections. Thus, Runx3 functions in a pioneering role to initialize and then ensure memory CTL differentiate.
2018-04-19 | GSE111143 | GEO
Project description:T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 controls de novo access to memory CTL-specific cistromes prior to the first cell division, and is essential for memory CTL differentiation. Runx3 specifically promotes accessibility of cis-acting regions highly enriched with IRF, bZIP and Prdm1-like family TF motifs, upregulates IRF4 and establishes feed-forward transcriptional circuits that induce fundamental CTL attributes in memory precursor cells. Runx3 drives uncoupling from the naïve cell state, but subsequently restrains terminal differentiation of nascent CTL by preventing high expression of the TF T-bet and slowing effector cell proliferation. Enforced Runx3 expression enhances memory CTL differentiation and increases their numbers during iterative infections. Thus, Runx3 functions in a pioneering role to initialize and then ensure memory CTL differentiate.
2018-04-19 | GSE111138 | GEO
Project description:T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 controls de novo access to memory CTL-specific cistromes prior to the first cell division, and is essential for memory CTL differentiation. Runx3 specifically promotes accessibility of cis-acting regions highly enriched with IRF, bZIP and Prdm1-like family TF motifs, upregulates IRF4 and establishes feed-forward transcriptional circuits that induce fundamental CTL attributes in memory precursor cells. Runx3 drives uncoupling from the naïve cell state, but subsequently restrains terminal differentiation of nascent CTL by preventing high expression of the TF T-bet and slowing effector cell proliferation. Enforced Runx3 expression enhances memory CTL differentiation and increases their numbers during iterative infections. Thus, Runx3 functions in a pioneering role to initialize and then ensure memory CTL differentiate.
2018-04-19 | GSE111135 | GEO
Project description:T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 controls de novo access to memory CTL-specific cistromes prior to the first cell division, and is essential for memory CTL differentiation. Runx3 specifically promotes accessibility of cis-acting regions highly enriched with IRF, bZIP and Prdm1-like family TF motifs, upregulates IRF4 and establishes feed-forward transcriptional circuits that induce fundamental CTL attributes in memory precursor cells. Runx3 drives uncoupling from the naïve cell state, but subsequently restrains terminal differentiation of nascent CTL by preventing high expression of the TF T-bet and slowing effector cell proliferation. Enforced Runx3 expression enhances memory CTL differentiation and increases their numbers during iterative infections. Thus, Runx3 functions in a pioneering role to initialize and then ensure memory CTL differentiate. This SuperSeries is composed of the SubSeries listed below.
2018-04-19 | GSE111149 | GEO
Project description:ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in EMT-dependent tumor metastasis. While the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is upregulated by activated T cells, specifically in the KLRG1hi effector CD8+ T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8+ T cells following primary and secondary infection with a severe impairment in the generation of the KLRG1hi effector-memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress CD127 and IL-2 in CD8+ T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box-sites in the ZEB2 gene and that T-bet and ZEB2 regulate similar gene-expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Taken together, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8+ T cells.
2015-09-19 | GSE72162 | GEO
Project description:Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTL, and that deletion or depletion of Dicer in mouse or human activated CD8+ T cells causes upregulation of perforin, granzyme and effector cytokines. Genome-wide analysis of miRNA changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of a miRNA network that controls perforin, eomesodermin (Eomes) and IL-2Ra expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation and antigenic stimulation. Overall our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation. Comparison of control and Dicer knock-out CTLs differentiated in vitro; Comparison of wild type CTLs differentiated in vitro with or without inflammatory stimuli; Comparison of effector and memory precursor CTLs isolated from mice infected with LCMV-Armstrong
2013-12-02 | E-GEOD-51393 | biostudies-arrayexpress
Project description:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.
2022-09-02 | PXD036457 | Pride