Identification of IL4 dependent genes involved in reinforcement stage of Th2 differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE16022 | GEO | 2010/03/30
SECONDARY ACCESSION(S): PRJNA115451
REPOSITORIES: GEO
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Project description:Naïve CD4+ T-helper cells differentiate into Th2 effector cells during asthma and helminth (worm) infection. Here, we report that mice lacking the transcription factor Bcl11b in mature CD4+ T-cells are incapable of mounting an effective Th2 response in asthma and worm infection, with a major reduction of Th2 cytokine secretion and GATA3 expression. We found that Bcl11b exerts its role in Th2 differentiation through several avenues: (1) association with intronic regions at the Gata3 locus, sustaining GATA3 expression; (2) binding to and restricting chromatin accessibility at the Il4 silencer, located at hypersensitivity site (HS) IV; and (3) restricting Runx3 expression by association with a regulatory region 5’ of Runx3. Thus, in the absence of Bcl11b, the reduction in GATA3 levels combined with increased Runx3 levels and activity at Il4 HS IV silencer and consequently diminished IL-4 expression. This results in reduced chromatin opening at the Th2 locus control region (LCR), Il13 and Il5 promoters, subsequently preventing expression of Th2 cytokine genes and Th2 differentiation. Our results establish a novel role for Bcl11b in the regulatory loop critical for licensing the Th2 program in vivo.
2018-05-09 | GSE99597 | GEO
Project description:Naïve CD4+ T-helper cells differentiate into Th2 effector cells during asthma and helminth (worm) infection. Here, we report that mice lacking the transcription factor Bcl11b in mature CD4+ T-cells are incapable of mounting an effective Th2 response in asthma and worm infection, with a major reduction of Th2 cytokine secretion and GATA3 expression. We found that Bcl11b exerts its role in Th2 differentiation through several avenues: (1) association with intronic regions at the Gata3 locus, sustaining GATA3 expression; (2) binding to and restricting chromatin accessibility at the Il4 silencer, located at hypersensitivity site (HS) IV; and (3) restricting Runx3 expression by association with a regulatory region 5’ of Runx3. Thus, in the absence of Bcl11b, the reduction in GATA3 levels combined with increased Runx3 levels and activity at Il4 HS IV silencer and consequently diminished IL-4 expression. This results in reduced chromatin opening at the Th2 locus control region (LCR), Il13 and Il5 promoters, subsequently preventing expression of Th2 cytokine genes and Th2 differentiation. Our results establish a novel role for Bcl11b in the regulatory loop critical for licensing the Th2 program in vivo.
2018-05-09 | GSE99598 | GEO
Project description:Mouse splenic naïve T cells were activated (with anti-CD3/CD28)and polarized towards the Th2 subtype with IL4 . Cells were collected at different time points during the differentiation and, at day 3 .5,were collected according to number of cell divisions and expression or absence of a specific differentiation marker.
2016-04-01 | E-MTAB-3543 | biostudies-arrayexpress
Project description:Naïve CD4+ T-helper cells differentiate into Th2 effector cells during asthma and helminth (worm) infection. Here, we report that mice lacking the transcription factor Bcl11b in mature CD4+ T-cells are incapable of mounting an effective Th2 response in asthma and worm infection, with a major reduction of Th2 cytokine secretion and GATA3 expression. We found that Bcl11b exerts its role in Th2 differentiation through several avenues: (1) association with intronic regions at the Gata3 locus, sustaining GATA3 expression; (2) binding to and restricting chromatin accessibility at the Il4 silencer, located at hypersensitivity site (HS) IV; and (3) restricting Runx3 expression by association with a regulatory region 5’ of Runx3. Thus, in the absence of Bcl11b, the reduction in GATA3 levels combined with increased Runx3 levels and activity at Il4 HS IV silencer and consequently diminished IL-4 expression. This results in reduced chromatin opening at the Th2 locus control region (LCR), Il13 and Il5 promoters, subsequently preventing expression of Th2 cytokine genes and Th2 differentiation. Our results establish a novel role for Bcl11b in the regulatory loop critical for licensing the Th2 program in vivo.
2018-05-09 | GSE99595 | GEO
Project description:Naive CD4+ T cells, sorted from PBMCs of grass-fed beef cattle, were stimulated with anti-bovine CD3 under Th2 differentiation conditions with or without Ostertagia ostertagi (OO) protein extract. Th1 differentiation conditions were included for comparison. The effect of recombinant bovine IL-4 (rbIL-4) and weakening TCR signal strength on Th2 differentiation were also tested. Flow cytometry, qPCR and proteomic assay were performed to analyze the differentiated cells.
The majority of differentiated cells expressed IFNgamma (a hallmark cytokine for Th1) and a small percentage of cells expressed both IFNgamma and IL-4 (a hallmark cytokine for Th2), indicating the presence of Th0 cells, as previously reported in cattle. While weakening TCR signal strength reduced Th2 cell expansion, adding rbIL-4 or OO protein extract enhanced Th2 cell expansion but without significant changes in IFNgamma and IL-4 expression. Proteomic data predicted that, as in mice and humans, bovine Th2 differentiation results from three upstream stimulation with CD3, CD28, and IL-4, which were inhibited when OO protein extract was added into the Th2 differentiation media. Importantly, protein profiling indicated that the addition of rbIL-4 enhanced IL-4 signaling but inhibited IL-12 signaling. Soon, we are planning to explore if other cytokines like IL-10 can be applied to optimize this Th2 differentiation in vitro.
Naive bovine CD4+ T cells differentiate into a mixed population containing a high percentage of IFNgamma producing cells and a small percentage of Th0 cells. Furthermore, bovine Th2 differentiation is sensitive to regulation such as by OO or rbIL-4.
2023-03-22 | MSV000091527 | MassIVE
Project description:Th2 cells enable humoral immunity and host-defense to parasites. Whereas IL-4 drives Th2 differentiation and IL-2 is important later in this process by augmenting IL4 chromatin accessibility, we demonstrate that IL-2 serves an essential early role in regulating IL-4Rα expression by inducing binding of Stat5a and Stat5b to the IL4ra locus, with sustained binding during Th2 differentiation. Although IL-4 induces IL-4Rα expression, TCR-induced IL-4Rα expression was unexpectedly normal in ILr-/- but profoundly diminished in IL2-/- T cells. Remarkably, enforced IL-4Rα expression rescued Th2 differentiation in IL2-/- cells. These results reveal a novel function for IL-2, with IL-2 via Stat5 providing an early signal for IL4ra induction, thereby priming cells for Th2 differentiation and promoting/maintaining IL-4Rα expression in Th2-committed cells. ChIP-seq experiments for Stat5a and Stat5b with an IgG control experiment for 8hr, 13hr and 2 rounds of Th2 differentiation. Keywords: ChIP-seq, Illumina, Th2 differentiation, Stat
2008-12-11 | GSE12346 | GEO
Project description:Th2 cells enable humoral immunity and host-defense to parasites. Whereas IL-4 drives Th2 differentiation and IL-2 is important later in this process by augmenting IL4 chromatin accessibility, we demonstrate that IL-2 serves an essential early role in regulating IL-4R? expression by inducing binding of Stat5a and Stat5b to the IL4ra locus, with sustained binding during Th2 differentiation. Although IL-4 induces IL-4R? expression, TCR-induced IL-4R? expression was unexpectedly normal in ILr-/- but profoundly diminished in IL2-/- T cells. Remarkably, enforced IL-4R? expression rescued Th2 differentiation in IL2-/- cells. These results reveal a novel function for IL-2, with IL-2 via Stat5 providing an early signal for IL4ra induction, thereby priming cells for Th2 differentiation and promoting/maintaining IL-4R? expression in Th2-committed cells. ChIP-seq experiments for Stat5a and Stat5b with an IgG control experiment for 8hr, 13hr and 2 rounds of Th2 differentiation. Keywords: ChIP-seq, Illumina, Th2 differentiation, Stat ChIP-seq experiments for Stat5a and Stat5b with an IgG control experiment for 8hr, 13hr and 2 rounds of Th2 differentiation. There are a total of 22 lanes of data for the three samples across the three time points.
2008-12-11 | E-GEOD-12346 | biostudies-arrayexpress
Project description:The type 2 cytokines, interleukin (IL)-4, IL-5 and IL-13 reside within a multi-gene cluster in mammals. These cytokines represent the hallmark of type 2 immune responses controlling parasites and promoting tissue repair, as well as causing allergic diseases. Both innate and adaptive lymphocytes secrete type 2 cytokines with discordant production spectra. We took a holistic structural and functional view of the type 2 cytokine locus before and after activation, comparing innate (ILC2) and adaptive (Th2) lymphocytes to understand mechanisms underlying their distinctive programs. Rapid induction of IL-5 dominates in ILC2, whereas IL-4 does so in Th2 cells. Using high-resolution chromatin conformation capture we found that global cellular chromatin architecture remained constant, whereas the type 2 cytokine locus rapidly remodeled. In ILC2, Il13 and Il5 loci were aligned in proximity whereas Il4 locus was insulated. In Th2 cells, Il4 and Il13 positioned in proximity while the Il5 locus remained distal. Select REs were individually deleted in mice to confirm cell-type specific and activation-dependent roles in type 2 responses in vivo. Thus, contrary to the premise that chromatin architecture plays a minimal role in steady-state gene induction, signal-dependent remodeling of 3D configuration underlies the discordant cytokine outputs in ILC2s versus Th2 cells.
2024-09-27 | GSE266345 | GEO
Project description:The type 2 cytokines, interleukin (IL)-4, IL-5 and IL-13 reside within a multi-gene cluster in mammals. These cytokines represent the hallmark of type 2 immune responses controlling parasites and promoting tissue repair, as well as causing allergic diseases. Both innate and adaptive lymphocytes secrete type 2 cytokines with discordant production spectra. We took a holistic structural and functional view of the type 2 cytokine locus before and after activation, comparing innate (ILC2) and adaptive (Th2) lymphocytes to understand mechanisms underlying their distinctive programs. Rapid induction of IL-5 dominates in ILC2, whereas IL-4 does so in Th2 cells. Using high-resolution chromatin conformation capture we found that global cellular chromatin architecture remained constant, whereas the type 2 cytokine locus rapidly remodeled. In ILC2, Il13 and Il5 loci were aligned in proximity whereas Il4 locus was insulated. In Th2 cells, Il4 and Il13 positioned in proximity while the Il5 locus remained distal. Select REs were individually deleted in mice to confirm cell-type specific and activation-dependent roles in type 2 responses in vivo. Thus, contrary to the premise that chromatin architecture plays a minimal role in steady-state gene induction, signal-dependent remodeling of 3D configuration underlies the discordant cytokine outputs in ILC2s versus Th2 cells.
2024-09-27 | GSE266529 | GEO
Project description:The type 2 cytokines, interleukin (IL)-4, IL-5 and IL-13 reside within a multi-gene cluster in mammals. These cytokines represent the hallmark of type 2 immune responses controlling parasites and promoting tissue repair, as well as causing allergic diseases. Both innate and adaptive lymphocytes secrete type 2 cytokines with discordant production spectra. We took a holistic structural and functional view of the type 2 cytokine locus before and after activation, comparing innate (ILC2) and adaptive (Th2) lymphocytes to understand mechanisms underlying their distinctive programs. Rapid induction of IL-5 dominates in ILC2, whereas IL-4 does so in Th2 cells. Using high-resolution chromatin conformation capture we found that global cellular chromatin architecture remained constant, whereas the type 2 cytokine locus rapidly remodeled. In ILC2, Il13 and Il5 loci were aligned in proximity whereas Il4 locus was insulated. In Th2 cells, Il4 and Il13 positioned in proximity while the Il5 locus remained distal. Select REs were individually deleted in mice to confirm cell-type specific and activation-dependent roles in type 2 responses in vivo. Thus, contrary to the premise that chromatin architecture plays a minimal role in steady-state gene induction, signal-dependent remodeling of 3D configuration underlies the discordant cytokine outputs in ILC2s versus Th2 cells.
2024-09-27 | GSE266347 | GEO