Intratumoral plasmid IL-12 expands CD8+ T cells and induces a CXCR3 signature in triple-negative breast tumors that sensitizes patient to anti-PD-1 therapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE157819 | GEO | 2021/09/01
REPOSITORIES: GEO
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2022-04-18 | GSE190651 | GEO
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:T cell receptors repertoire sequencing of the human CD8+ naive subsets (CXCR3-,CXCR3+)
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Project description:Background: The function of hematopoietic stem cells (HSC) is regulated by HSC internal signaling pathways and their microenvironment. Chemokines and chemokine ligands play important roles in the regulation of HSC function. Yet, their functions in HSC are not fully understood. Methods: We established Cxcr3 and Cxcl10 knockout mouse models (Cxcr3-/- and Cxcl10-/-) to analyze the roles of Cxcr3 or Cxcl10 in regulating HSC function. The cell cycle distribution of LT-HSC was assessed via flow cytometry. Cxcr3-/-and Cxcl10-/-stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. To study the effects of Cxcr3 or Cxcl10 deficient bone marrow microenvironment, we transplanted CD45.1 donor cells into Cxcr3-/-or Cxcl10-/- recipient mice (CD45.2) and examined donor-contributed hematopoiesis. Results: Deficiency of Cxcl10 and its receptor Cxcr3 led to decreased BM cellularity in mice, with a significantly increased proportion of LT-HSC. Cxcl10-/- stem/progenitor cells showed reduced self-renewal capacity in the secondary transplantation assay. Notably, Cxcl10-/- donor-derived cells preferentially differentiated into B lymphocytes, with skewed myeloid differentiation ability. Meanwhile, Cxcr3-deficient HSCs demonstrated a reconstitution disadvantage in secondary transplantation, but the lineage bias was not significant. Interestingly, the absence of Cxcl10 or Cxcr3 in bone marrow microenvironment did not affect HSC function. Conclusions: The Cxcl10 and Cxcr3 regulate the function of HSC, including self-renewal and differentiation, adding to the understanding of the roles of chemokines in the regulation of HSC function.
2024-07-25 | GSE272747 | 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).
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Project description:CD4+Foxp3+ Treg cells are essential for maintaining self-tolerance and preventing excessive immune responses. In the context of Th1 immune responses, co-expression of the Th1 transcription factor T-bet with Foxp3 is essential for Treg cells to control Th1 responses. T-bet-dependent expression of CXCR3 directs Tregs to the site of inflammation, however, the suppressive mediators enabling effective control of Th1 responses at this site are unknown. In this study, we determined the signature of CXCR3+ Treg cells arising in Th1 settings and defined universal features of Treg cells in this context using multiple Th1-dominated models. Our analysis defined a set of Th1-specific co-inhibitory receptors that are specifically expressed in Treg cells during Th1 immune responses. Among these, we identified the novel co-inhibitory receptor CD85k as a functional mediator of the enhanced suppression of Th1 effector cells by CXCR3+ Treg cells.
2018-06-30 | E-MTAB-6156 | biostudies-arrayexpress
Project description:Cancer-associated fibroblasts promote the development of many primary malignancies, but their function in metastatic progression is poorly understood. Here, we demonstrate that colonization of the lungs by metastatic breast cancer cells induces an inflammatory phenotype in lung fibroblasts. CXCL9 and CXCL10 are induced in an NFκB-dependent manner in metastasis-associated fibroblasts in response IL-1α and IL-1β secreted by disseminated breast cancer cells. We find that the chemokine receptor CXCR3, that binds CXCL9/10, is expressed in a small subset of breast cancer cells that exhibits greater tumor-initiating ability when co-transplanted with fibroblasts. CXCR3-expressing cancer cells maintain JNK signaling that drives IL-1A/B expression, and thus rendering this subpopulation efficient in both inducing CXCL9/10 in lung fibroblasts and responding to the chemokines. Importantly, disruption of the CXCL9/10-CXCR3 axis significantly reduces metastatic colonization in xenograft and syngeneic mouse models suggesting an essential role of this paracrine crosstalk in metastatic progression and a potential therapeutic vulnerability for the treatment of metastatic breast cancer.
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Project description:Transcriptional analysis of murine CXCR3+ vs. CXCR3- peritoneal cavity B cells 8 days following infection with Ehrlichia muris.
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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:HIV-1-specific broadly-neutralizing antibodies (bnAb) typically develop in individuals with continuous high-level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-level viremia may be important for designing bnAb-inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-1 controllers was associated with a relative enrichment of circulating CXCR5+ CXCR3+ PD-1Lo CD4 T cells. These CXCR3+ PD-1Lo Tfh-like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-21 and support B cells. In addition, these CXCR3+ PD-1Lo Tfh-like cells contain higher proportions of stem cell-like memory T cells, and upon antigenic stimulation differentiated into PD-1Hi Tfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5+ CXCR3+ PD-1Lo cells represent a dendritic cell-primed precursor cell population for PD-1Hi Tfh-like cells that may contribute to the generation of bnAbs in the absence of high–level viremia.
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