RNA-seq of TCR-stimulated CD4⁺ T cells from SKG mice treated with the Nr4a1 agonist Cytosporone B
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE312091 | GEO | 2026/02/14
REPOSITORIES: GEO
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Project description:Th17 cells are enriched by sorting FR4-CD4+ T cells from SKG mice. A large number of Th17 cells also develop spontaneously when CD4+ T cells from IFN-g-deficient (IFN-g-/-) BALB/c mice are transferred to T cell-deficient RAG2-deficient (RAG2-/-) mice and subjected to homeostatic proliferation, whereas they fail to develop in similar transfer of IL-6-deficient (IL-6-/-) CD4+ T cells to IL-6-/- RAG2-/- mice. To explore the functional molecules specifically expressed by Th17 cells, we conducted Gene Microarray analysis between 10-month-old SKG FR4-CD4+ cells and age-matched BALB/c FR4-CD4+ cells, and between IFN-g-/- CD4+ cells transferred to RAG2-/- mice and IL-6-/- CD4+ T cells transferred to IL-6-/- RAG2-/- mice. The analysis revealed that 1,556 and 115 genes were up-regulated in 10-month-old SKG FR4-CD4+ and IFN-g-/- CD4+ T cells after homeostatic proliferation, respectively, with 29 genes shared by the two groups of genes. The 29 genes included those encoding cytokines, chemokines, and their receptors, such as IL-1 receptor type1 (IL-1R1), IL-17, IL-22, IL-21, CCR6, and CCL20. Experiment Overall Design: We conducted Gene Microarray analysis between 10-month-old SKG FR4-CD4+ cells and age-matched BALB/c FR4-CD4+ cells, and between IFN-g-/- CD4+ cells transferred to RAG2-/- mice and IL-6-/- CD4+ T cells transferred to IL-6-/- RAG2-/- mice using GeneChip Mouse Genome 430 2.0 Array (Affymetrix). Each gruop has three replicates.
2008-06-16 | E-GEOD-9316 | biostudies-arrayexpress
Project description:T helper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We performed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferentiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4+ T cells. We demonstrate that cross-talk between TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.
2025-09-19 | GSE234595 | GEO
Project description:T helper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We performed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferentiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4+ T cells. We demonstrate that cross-talk between TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.
2025-09-19 | GSE234597 | GEO
Project description:T helper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We performed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferentiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4+ T cells. We demonstrate that cross-talk between TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.
2025-09-19 | GSE234596 | GEO
Project description:Purpose: The goals of this study were to study the transcriptome and TCR repertoire of naive CD4 T cells before the induction of arthritis in the SKG and wild-type (WT) mouse with eGFP-Nur77 as a reporter of antigen stimulation (SKGNur and WTNur). Methods: Bulk RNA sequencing was used to generate the mRNA profiles for the top 10% and bottom 10% of GFP expressing cells from three SKGNur and three WTNur BALB/c mice resulting in 12 samples overall (3 WT Low, 3 WT High, 3 SKG Low, 3 SKG High) using the Truseq Stranded mRNA kit followed by sequencing on a HiSeq 2500 sequencer. The sequence reads that passed quality filters were aligned with STAR and then analyzed with DESeq2. Results: We mapped about 38,000,000 million reads per sample to the mouse genome (mm10). The differential expression pairwise comparisons (WT Low v WT High, WT Low v SKG Low, SKG Low v SKG High, and WT High v SKG High) generated a collection of 991 differentially expressed genes with log2FC >1 and Benjamini-Hochberg adjusted p value < 0.05. Hierarchical clustering of differentially expressed genes uncovered six modules of gene expression which highlighted heterogeneity within the naive CD4 T cell compartment and transcriptional signatures associated with the SKG High samples. Methods: Single cell RNA gene expression and TCR sequencing libraries were generated for the top 10% and bottom 10% of GFP expressing cells from two SKGNur and two WTNur BALB/c mice resulting in 8 samples overall (2 WT Low, 2 WT High, 2 SKG Low, 2 SKG High) using the 5' 10x single cell 5"+V(D)J v1 kit and were sequenced on a NovaSeq 6000 sequencer. The reads were aligned using cellranger and analyzed using a combination of single cell tools including scanpy and scvelo. Results: We mapped about 785,000,000 sequence reads and about 379,000,000 sequence reads per sample for the gene expression and TCR libraries to the mouse genome (build mm10 with the addition of the eGFP transcript) and TCR reference (vdj GRCm38 v 3.1.0), respectively, using cellranger. We identified 31,054 transcripts across 101,869 cells and recovered paired TRA and TRB chains from more than 80% of cells. After filtering cells and genes by our quality control metrics, we identified 1119 highly variable genes which were used for PCA analysis to create a nearest neighbors graph for leiden clustering and UMAP projection. We identified 13 clusters that we collapsed into 9 cell sub-types. Within the cluster (T.4_Nr4a1) exclusively expressing our marker gene of interest, Nr4a1, we found that SKG High cells upregulated TCR signaling genes despite their impaired impaired TCR signaling ability due to a Zap70 mutation. Within the T.4Nr4a1 cluster we found two states of acute to chronic TCR signaling, marked by Egr2 and Tnfrsf9, and we used trajectory inference to uncover a continuum of cell states with these acute to chronic TCR signaling states as the endpoints. Interestingly, SKG High cells in the T.4 Nr4a1 cluster seemed arrested in the earlier more acute TCR signaling state suggesting they are unable to appropriately fully upregulate the chronic TCR signaling and more anergic cell state. We also uncovered TRBV restriction within the SKG High samples and specifically within the SKG High cells within the T.4 Nr4a1 cluster that seems to be driven by a failure of negative selection by endogenously expressed super antigens from MMTVs present in the BALB/c mouse. Thus the naive CD4 T cell compartment within the SKG High cells are poised to enter into a reactive immune response via both a unique transcriptomic and TCR repertoire which may underlie the mechanism of high arthritogenic potential of these cells.
2024-04-05 | GSE185577 | GEO
Project description:Foxp3 is indispensable for Treg suppressive function, but the stability of Foxp3 has been controversial. In autoimmune arthritis, Th17 cells play a critically important pathological role, but the origin of Th17 cells remains unknown We used microarrays to detail the global programme of gene expression of Th17 cells originated from Foxp3+T cells compared to conventional naive CD4+T cells derived Th17 cells. We also take samples of Treg cells and Th0 cells for the experimetnatl control. Each T cell subset after the culture was subjected to RNA extraction and hybridization on Affymetrix microarrays.
2013-12-21 | E-GEOD-48428 | biostudies-arrayexpress
Project description:Th17 cells are enriched by sorting FR4-CD4+ T cells from SKG mice. A large number of Th17 cells also develop spontaneously when CD4+ T cells from IFN-g-deficient (IFN-g-/-) BALB/c mice are transferred to T cell-deficient RAG2-deficient (RAG2-/-) mice and subjected to homeostatic proliferation, whereas they fail to develop in similar transfer of IL-6-deficient (IL-6-/-) CD4+ T cells to IL-6-/- RAG2-/- mice. To explore the functional molecules specifically expressed by Th17 cells, we conducted Gene Microarray analysis between 10-month-old SKG FR4-CD4+ cells and age-matched BALB/c FR4-CD4+ cells, and between IFN-g-/- CD4+ cells transferred to RAG2-/- mice and IL-6-/- CD4+ T cells transferred to IL-6-/- RAG2-/- mice. The analysis revealed that 1,556 and 115 genes were up-regulated in 10-month-old SKG FR4-CD4+ and IFN-g-/- CD4+ T cells after homeostatic proliferation, respectively, with 29 genes shared by the two groups of genes. The 29 genes included those encoding cytokines, chemokines, and their receptors, such as IL-1 receptor type1 (IL-1R1), IL-17, IL-22, IL-21, CCR6, and CCL20. Keywords: cell type comparison
2007-10-17 | GSE9316 | GEO
Project description:T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy.
2019-06-10 | GSE132477 | GEO
Project description:<p>We use next generation sequencing to investigate the different transcriptomes of closely related CD4+ T-cells from healthy human donors to elucidate the genetic programs that underlie their specialized immune functions. Six cell types were included: Regulatory T-cells (CD25hiCD127low/neg with >95% FOXP3+ purity), regulatory T-cells activated using PMA/ionomycin, CD25-CD45RA+ ('naive' helper T-cells), CD25-CD45RO+ ('memory' helper T-cells), activated Th17 cells (>98% IL17A+ purity) and activated IL17-CD4+ T-cells (called 'ThPI'). Poly-T capture beads were used to isolate mRNA from total RNA, and fragment sizes of ~200 were sequenced from both ends on Illumina's genome analyzer. We confirm many of the canonical signature genes of T-cell populations, but also discover new genes whose expression is limited to specific CD4 T-cell lineages, including long non-coding RNAs. Additionally, we find that genes encoded at loci linked to multiple human autoimmune diseases are enriched for preferential expression upon T-cell activation, suggesting that an aberrant response to T-cell activation is fundamental to pathogenesis.</p>
| phs000626 | dbGaP
Project description:T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy.
2019-06-10 | GSE132476 | GEO