CXCR3 regulates stem and proliferative CD8+ T cells during chronic infection by promoting interactions with DCs in splenic bridging channels
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA777607 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16763848.fastq.gz | Fastqsanger.gz | |||
| SRR16763849.fastq.gz | Fastqsanger.gz | |||
| SRR16763850.fastq.gz | Fastqsanger.gz | |||
| SRR16763851.fastq.gz | Fastqsanger.gz | |||
| SRR16763852.fastq.gz | Fastqsanger.gz |
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Project description:Production of armed effector CD8+ T cells during persistent infection requires a stable pool of stem-like cells that can give rise to short-lived effector T cells via a proliferative intermediate population. In chronic infection models marked by T cell exhaustion, this process can be transiently induced by check-point blockade, but it occurs spontaneously and continuously in the spleens of mice chronically infected with the protozoan intracellular parasite, Toxoplasma gondii, providing a unique opportunity to examine the steps in the differentiation process. Using this model, we observed distinct locations and gene expression patterns for stem-like memory cells, proliferative intermediate cells, and terminally differentiated effector cells, implying a link between differentiation and discrete anatomical niches in the spleen. Loss of the chemokine receptor CXCR3 on parasite-specific T cells did not impair their white pulp to red pulp migration but reduced their interactions with CXCR3 ligand-producing type 2 conventional DCs in the bridging channels and impaired their transition from memory to intermediate states, leading to a build up of memory T cells localized to the red pulp. These results demonstrate a critical role for CXCR3 during chronic infection by increasing T cell exposure to differentiation-inducing signals during red pulp migration, providing a dynamic and flexible mechanism for modulating effector differentiation in response to environmental signals.
2021-11-05 | GSE187545 | GEO
Project description:Production of effector CD8+ T cells during persistent infection requires a stable pool of stem-like cells that can give rise to effector cells via a proliferative intermediate population. In infection models marked by T cell exhaustion, this process can be transiently induced by checkpoint blockade but occurs spontaneously in mice chronically infected with the protozoan intracellular parasite Toxoplasma gondii. We observe distinct locations for parasite-specific T cell subsets, implying a link between differentiation and anatomical niches in the spleen. Loss of the chemokine receptor CXCR3 on T cells does not prevent white pulp-to-red pulp migration but reduces interactions with CXCR3 ligand-producing dendritic cells (DCs) and impairs memory-to-intermediate transition, leading to a buildup of memory T cells in the red pulp. Thus, CXCR3 increases T cell exposure to differentiation-inducing signals during red pulp migration, providing a dynamic mechanism for modulating effector differentiation in response to environmental signals.
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Project description:We performed bulk RNA sequencing on murine CXCR3+ and CXCR3-negative live singlet IgM+ IgD-neg CD19+ CD138-neg (B1 B cell-like) peritoneal cavity B cells to compare the transcriptomes of the two populations following i.p. infection with the intracellular bacterium Ehrlichia muris. Total RNA was extracted and sequenced, followed by pseudoalignment, quality assessment, normalization, and analysis of differential gene expression. The CXCR3+ B1 B cell-like population was highly enriched for genes involved in proliferation, metabolism, and cell division, whereas the CXCR3- B1 B cell-like population transcriptionally resembled canonical B1 B cells and did not appear to be proliferative. These results suggest local proliferation of CXCR3+ B cells occurs in the peritoneal cavity during acute infection with an intracellular bacterium.
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Project description:Plexiform neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models which invariably form neurofibroma to those with inflammation driven by EGFR overexpression which rarely progresses to neurofibroma. We find that the chemokine Cxcl10 is uniquely up-regulated in NF1 mice that invariably develop neurofibroma. Global deletion of the CXCL10 receptor, Cxcr3, prevented neurofibroma development in these neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in neurofibroma initiation.
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Project description:Plexiform neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models which invariably form neurofibroma to those with inflammation driven by EGFR overexpression which rarely progresses to neurofibroma. We find that the chemokine Cxcl10 is uniquely up-regulated in NF1 mice that invariably develop neurofibroma. Global deletion of the Cxcl10 receptor Cxcr3 prevented neurofibroma development in these neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in neurofibroma initiation.
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Project description:T cell receptors repertoire sequencing of the human CD8+ naive subsets (CXCR3-,CXCR3+)
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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.
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Project description:Aspergillus fumigatus, a ubiquitous mold, is a common cause of invasive aspergillosis (IA) in immunocompromised patients. Host defense against IA relies on lung-infiltrating neutrophils and monocyte-derived dendritic cells (Mo-DCs). Here, we demonstrate that plasmacytoid dendritic cells (pDCs), which are prototypically antiviral cells, participate in innate immune crosstalk underlying mucosal antifungal immunity. Aspergillus-infected murine Mo-DCs and neutrophils recruited pDCs to the lung by releasing the CXCR3 ligands, CXCL9 and CXCL10, in a Dectin-1 and Card9- and type I and III interferon signaling-dependent manner, respectively. During aspergillosis, circulating pDCs entered the lung in response to CXCR3-dependent signals. Via targeted pDC ablation, we found that pDCs were essential for host defense in the presence of normal neutrophil and Mo-DC numbers. Although interactions between pDC and fungal cells were not detected, pDCs regulated neutrophil NADPH oxidase activity and conidial killing. Thus, pDCs act as positive feedback amplifiers of neutrophil effector activity against inhaled mold conidia.
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