CXCL10 regulates heterogenity of the CD8+ T cell response and viral set point during chronic infection
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ABSTRACT:
PROVIDER: PRJNA770662 | ENA |
REPOSITORIES: ENA
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Project description:CD8+ T cell responses to chronic infection are sustained by stem-like cells, which differentiate into effector-like cells mediating some level of pathogen control; however persistent antigen progressively impairs their effector functions. Understanding the molecular control of stem-like cell differentiation to improve durability of functional T cell responses has important therapeutic implications. Here, we found that the chemokine receptor CXCR3 was highly expressed on viral-specific stem-like CD8+ T cells and that one of its ligands, CXCL10, regulated the persistence and heterogeneity of responding CD8+ T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 was produced by inflammatory monocytes and fibroblasts of the splenic red pulp where it granted stem-like cells access to signals promoting differentiation and limited their exposure to pro-survival niches in the white pulp. Consequently, the magnitude of functional CD8+ T cell responses was greater in Cxcl10-/- mice and was associated with a lower viral set point.
2021-10-13 | GSE185746 | GEO
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Project description:Mutations in the RMRP gene are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in the RMRP gene lead to skeletal dysplasia. Viperin is a known substrate of RMRP. Since chondrogenic differentiation of the growth plate is required for development of the long bones, we hypothesized that viperin functions as a chondrogenic regulator downstream of RMRP. Viperin protein is expressed throughout the stages of chondrogenic differentiation in vivo. Viperin gene expression is increased during knockdown of Rmrp RNA in the ATDC5 model for chondrogenic differentiation. Viperin is expressed during ATDC5 chondrogenic differentiation. Viperin knockdown reduces, while viperin overexpression increases overall protein secretion, with CXCL10 identified as a potential target via mass spectrometry-proteomics. CXCL10 protein expression is reduced during knockdown and increased during overexpression of viperin and CXCL10 protein expression coincides with viperin expression in ATDC5 chondrogenic differentiation. Viperin knockdown induces, while viperin overexpression reduces TGFβ activity. Furthermore, viperin knockdown conditioned media increases, while viperin overexpression conditioned media reduces chondrogenic differentiation of ATDC5 cells. TGFβ target genes Pai1 and Smad7 are increased during knockdown and reduced during overexpression of viperin. Moreover, TGFβ activity is reduced when differentiating ATDC5 cells are exposed to CXCL10 and, acting as a viperin overexpression mimic, CXCL10 similarly reduces chondrogenic differentiation of ATDC5. Lastly, we show that in CHH patient cells, RMRP expression is reduced and viperin expression is increased, coinciding with reduced chondrogenic differentiation and increased CXCL10 expression, possibly explaining the CHH phenotype. Together our data show that viperin may play a pivotal role in chondrogenic differentiation, with potential consequences for cartilage-hair hypoplasia pathobiology.
2019-02-15 | PXD006999 | Pride
Project description:Clinical approaches to treat advanced melanoma include immune therapies, whose benefits depend on tumor-reactive T-cells to infiltrate metastases. However, most tumors lack significant immune infiltration prior to therapy, and some immune therapies are hindered by a persistent lack of immune cell infiltration. CXCL10 has been implicated as a critical chemokine supporting T-cell migration into tumors; thus agents that induce CXCL10 in tumors may improve patient responses to systemic immune therapy. We find that melanoma cells treated with TLR2/6 agonists (MALP-2 or FSL-1) and interferon-gamma (IFNgamma) upregulate CXCL10 production, when compared to IFNgamma treatment alone or no treatment. Gene profiling of melanoma cells lines treated with TLR2/6 agonists and IFNgamma demonstrate that a selective profile of genes are induced which may be favorable for promoting immune cell infiltration of tumors. TLR2 and TLR6 are widely expressed on human melanoma cells, and treatment of melanoma cells with TLR2/6 agonists and IFNgamma does not hinder melanoma cell apoptosis or promote proliferation. Furthermore, melanoma cells from surgically resected patient tumors upregulate CXCL10 production after treatment with TLR2/6 agonists and IFNgamma when compared to treatment with either agent alone. Collectively, these data identify TLR2/6 agonists and IFNgamma as a novel target for promoting CXCL10 production directly from melanoma cells. Samples from four human melanoma cell lines, VMM1 (n=6), DM13 (n=6), DM93 (n=6) and VMM39 (n=6), were treated with media alone, MALP-2 (TLR2/6 agonist), FSL-1 (TLR2/6 agonist), IFNgamma alone, MALP-2 and IFNgamma, or FSL-1 and IFNgamma.
2015-11-22 | E-GEOD-64506 | biostudies-arrayexpress
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Project description:Macrophage heterogenity in liver and adipose during obesity
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Project description:Clinical approaches to treat advanced melanoma include immune therapies, whose benefits depend on tumor-reactive T-cells to infiltrate metastases. However, most tumors lack significant immune infiltration prior to therapy, and some immune therapies are hindered by a persistent lack of immune cell infiltration. CXCL10 has been implicated as a critical chemokine supporting T-cell migration into tumors; thus agents that induce CXCL10 in tumors may improve patient responses to systemic immune therapy. We find that melanoma cells treated with TLR2/6 agonists (MALP-2 or FSL-1) and interferon-gamma (IFNgamma) upregulate CXCL10 production, when compared to IFNgamma treatment alone or no treatment. Gene profiling of melanoma cells lines treated with TLR2/6 agonists and IFNgamma demonstrate that a selective profile of genes are induced which may be favorable for promoting immune cell infiltration of tumors. TLR2 and TLR6 are widely expressed on human melanoma cells, and treatment of melanoma cells with TLR2/6 agonists and IFNgamma does not hinder melanoma cell apoptosis or promote proliferation. Furthermore, melanoma cells from surgically resected patient tumors upregulate CXCL10 production after treatment with TLR2/6 agonists and IFNgamma when compared to treatment with either agent alone. Collectively, these data identify TLR2/6 agonists and IFNgamma as a novel target for promoting CXCL10 production directly from melanoma cells.
2015-11-22 | GSE64506 | GEO
Project description:Tumor necrosis factor alpha induces vascular permeability, playing an important role in inflammation. Also, TNF-induced vascular leakage is involved in the increased extravasation of nanoparticle formulated chemotherapeutics improving drug delivery and subsequently tumor response, and we found a positive correlation between the presence of pericytes in the tumor-associated vasculature and TNF-induced leakage. RNA sequencing and pathway analysis of TNF-stimulated versus non-stimulated pericytes and endothelial cells show significant upregulation of several pathways involving interferon regulating pathways with a high expression of CXCL10, also known as Interferon gamma-inducible protein 10 (IP-10) in TNF-stimulated pericytes. In addition, CXCL10 protein production was significantly increased in conditioned medium from TNF-exposed pericytes compared to the other conditions. In our animal studies, we observed that tumor types with high pericyte covered vessels show enhanced permeability when exposed to TNF, which can be blocked with a neutralizing CXCL10 antibody. Vice versa, tumors with vessels low in pericyte number do not respond to TNF, i.e., do not express elevated permeability. Importantly, this lack of pericyte coverage can be compensated by co-administration of CXCL10. Our finding reveals a mechanism where TNF induces CXCL10 release from pericytes, being at the basis of increased permeability and thus vascular leakage.
2022-07-01 | GSE203505 | GEO
Project description:Plasmacytoid dendritic cells (pDCs) play a critical role in bridging the innate and adaptive immune systems. pDCs are specialized type I interferon (IFN) producers, which has implicated them as initiators of autoimmune pathogenesis. However, little is known about the down-stream effectors of type I IFN signaling that amplify autoimmune responses. Here we have used a chemokine reporter mouse to determine the CXCR3 ligand responses in DCs subsets. Following TLR7 stimulation conventional type 1 and type 2 DCs (cDC1 and cDC2 respectively) uniformly upregulate CXCL10. By contrast, the proportion of chemokine positive pDCs was significantly less, and stable CXCL10+ and CXCL10 - populations could be distinguished. CXCL9 expression was induced in all cDC1s, in half of the cDC2 but not by pDCs. In all DC subsets, type I IFNs were the main inducer of CXCR3 chemokines, as IFNAR receptor blocking or deficiency completely abrogated reporter expression. Chemoki ne producing potential was not concordant with the previously identified markers of pDC heterogeneity. Finally, we show that CXCL10+ and CXCL10 - populations are transcriptionally distinct, expressing unique transcriptional regulators, IFN signaling molecules, chemokines, cytokines and cell surface markers. This work highlights CXCL10 as a downstream effector of type I IFN signaling and suggests a division of labor in pDCs subtypes that likely impacts their function as effectors of viral responses and as drivers of inflammation.
2018-06-24 | GSE113770 | GEO