RNAseq of CD8 T-cells stimulated with CXCR3 chemokines
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ABSTRACT:
PROVIDER: PRJNA792600 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17336100_1.fastq.gz | Fastqsanger.gz | |||
| SRR17336100_2.fastq.gz | Fastqsanger.gz | |||
| SRR17336101_1.fastq.gz | Fastqsanger.gz | |||
| SRR17336101_2.fastq.gz | Fastqsanger.gz | |||
| SRR17336102_1.fastq.gz | Fastqsanger.gz |
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Project description:G protein-coupled receptors (GPCRs) interact with many transducers like G proteins and β-arrestins. Some GPCR agonists act as “biased agonists” which preferentially activate specific signaling transducers over others, leading to unique signaling profiles. The chemokine system, a subfamily of GPCRs that plays a critical role in inflammatory diseases, serves as an endogenous example of biased agonism where over 50 different chemokines ligands and 20 receptors interact promiscuously. In this study, we sought to determine the three different chemokines of the chemkoine receptor CXCR3 generate different transcriptional responses in primary CD8+ T cells. Using RNAseq on CD8+ T cells stimulated with either vehicle control, CXCL9, CXCL10, or CXCL11, the endogenous chemokines of CXCR3, we found that the CXCR3 chemokines promoted unique transcriptional responses that are predicted to differentially regulate inflammatory pathways. We observed significant changes in global transcriptional activation, detecting approximately 48000 transcripts, 887 of which varied by chemokine treatment. There was a high degree of replicability between biological replicates. The overwhelming majority of differentially expressed genes (DEGs) increased in transcript level following chemokine treatment. Compared to vehicle control, CXCL11 demonstrated the largest number of DEGs. Importantly, CXCL11 and CXCL10 demonstrate unique transcriptional profiles where the majority of DEGs were only found following treatment with each specific chemokine, rather than being shared across chemokines. These data contrast with that observed at CXCL9 – although it promoted a significant amount of transcriptional regulation, approximately 66% of CXCL9-induced DEGs were shared with CXCL11 and/or CXCL10.
2022-07-23 | GSE192679 | GEO
Project description:The presented data corresponds to the analysis of two discrete subsets of human CD8+ naive T cells, defined by positive and negative expression of the chemokine receptor CXCR3 (TNR3-, TNR3+). In this study we demonstrated that these subsets have different potential to generate fully-differentiated effector T cells following antigen-specific stimulation. The performed systematic immune repertoire analysis (T cell receptor beta chain (TRB)) of the sorted cell subsets revealed diverse physico-chemical properties of TRB CDR3 sequences suggesting enhanced TCR self-reactivity in human TNR3+ cells. In total, we analyzed 74 samples (from 11 patients, 3 replicates of each cell subset (excluding one missing replicate) and additionally for 3 patients CD8+ memory T cells in 3 replicates). We used the Human TCR Profiling Kit (MiLaboratory LLC) for sequencing libraries preparation and Illumina NextSeq 550 sequencing (150+150bp) followed by the demultiplexing procedure using MIGEC software (https://github.com/mikessh/migec).
2019-10-17 | E-MTAB-7638 | biostudies-arrayexpress
Project description:T cell receptors repertoire sequencing of the human CD8+ naive subsets (CXCR3-,CXCR3+)
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Project description:Purpose: A growing body of evidence highlights the association of exuberant CD8+ T cell responses with influenza acute lung injury. Given their indispensable role in viral clearance, we studied the double-edged function of CD8+ T cells as a bridge between infection resolution and lung pathology. Methods: we performed scRNA-Seq to study the cellular heterogeneity and regulation of cellular response in CD8+ T cells during peak viral (day 7) and post-viral resolution phase (day 14). Results: Our single-cell RNA-Seq data reveal significant differences in CD8+ T cell heterogeneity during different stages of influenza infection (peak viral load vs. infection resolved state). While CXCR3hi CD8+ T effector memory (Tem) was associated with a more robust cytotoxic response (compared to CXCR3low CD8+ T central memory, Tcm), both CD8+ Tem and Tcm exhibited equally potent effector function. The ablation of CXCR3 mitigates lung injury without affecting viral clearance. IFN-gamma was dispensable to the recruitment and regulation of cytotoxic response of CXCR3+ CD8+ T cells. Using scRNAseq, we identified unique regulons associated with regulating cytotoxic response in CXCR3hi CD8+ T cells. Conclusions: Collectively, our data identify CXCR3 as a potential therapeutic target to curb lung injury during influenza pathogenesis.
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Project description:Chemokine receptors (CKRs), a class of G protein-coupled receptors (GPCRs), interact with transducers like G proteins and β-arrestins. Many chemokines act as “biased agonists” that activate certain transducers over others. There has been limited success in pharmacologically targeting CKRs, with little evidence that differential receptor phosphorylation, or “phosphorylation barcodes,” direct biased responses. Here, we used mass spectrometry to demonstrate that CXCR3 chemokines generate different phosphorylation barcodes associated with differential activation of transducers. Chemokine stimulation resulted in distinct changes throughout the kinome in global phosphoproteomic studies. Mutation of CXCR3 phosphosites altered β-arrestin conformation and activation in molecular dynamics simulations. T-cells expressing phosphorylation-deficient CXCR3 mutants resulted in agonist- and receptor-specific chemotactic profiles not completely explained by engagement of G proteins and β-arrestins. Our results demonstrate that CXCR3 chemokines act as biased agonists through differential encoding of phosphorylation barcodes, and highlight the limitations of assessing GPCR physiology with proximal effector activity alone.
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Project description:Coordinated communication among pancreatic islet cells is necessary for the maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β-cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β-cell stress. We report that pro-inflammatory β-cell small EVs (cytoEV) induce β-cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8+ T-cells and macrophages. Proteomic analysis of cytoEV revealed an enrichment of the chemokine, CXCL10, with surface topological analysis depicting CXCL10 as membrane-bound on cytoEV to facilitate direct binding to CXCR3 receptors on the surface of β-cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β-cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. Collectively, this work implicates the significant role of pro-inflammatory β-cell derived small EVs in modulating β-cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.
2021-08-25 | PXD026998 | Pride
Project description:The overall goal of this study was to understand the change in antigen-stimulated gene expression in CD8 T cells upon ablation of a transcriptional coactivator Carm1 by CRISPR-Cas9 method. Seven days following editing, OT-I CD8 T cells were co-cultured for 24 hours with B16F10-Ova tumor cells. RNA-seq analysis demonstrated changes in gene expression, including upregulation of 1,143 genes and downregulation of 1,199 genes in Carm1 KO compared to control T cells. Upregulated genes encoded chemokine receptors that mediate T cell recruitment into tumors (Cxcr3) and key genes required for maintenance of memory T cell populations (transcription factor genes Tcf7, Myb, Bcl6; surface receptor Cd27). Downregulated genes included those associated with terminal differentiation (Klrg1), inhibition of cytokine signaling (Socs1, Socs3) and T cell dysfunction within tumors (Egr2, Eomes).
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