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Interferon-gamma critically determines dendritic cell function

ABSTRACT: A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects IFN-gamma on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of human peripheral-blood monocytes into moDCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4, interferon-gamma (IFN-gamma) induces moDC maturation and up-regulates the co-stimulatory markers CD80, CD86, CD95, and MHC Class I, enabling moDCs to effectively generate antigen-specific CD4+ and CD8+ T cell responses for multiple viral and tumor antigens. Interestingly, early exposure of monocytes to high concentrations of IFN-gamma promotes monocyte differentiation into macrophages, despite the presence of GM-CSF and IL-4. However, under low concentrations of IFN-gamma, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-gamma and an inability to generate effective antigen-specific CD4+ and CD8+ T cell responses compared to standard moDCs. Monocytes differentiated in the presence of low levels of IFN-gamma downregulate IFN-gamma receptor expression, impairing their response to an inflammatory rechallenge. These findings demonstrate the ability of IFN-gamma to impart differential programs on human moDCs which shape the antigen-specific T cell responses they induce. Timing and intensity of exposure to IFN-gamma can thus determine whether moDCs are tolerogenic or immunostimulating.

ORGANISM(S): Homo sapiens

PROVIDER: GSE47621 | GEO | 2014/06/01

SECONDARY ACCESSION(S): PRJNA206891

REPOSITORIES: GEO

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Interferon-gamma critically determines dendritic cell function

Project description:A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects IFN-gamma on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of human peripheral-blood monocytes into moDCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4, interferon-gamma (IFN-gamma) induces moDC maturation and up-regulates the co-stimulatory markers CD80, CD86, CD95, and MHC Class I, enabling moDCs to effectively generate antigen-specific CD4+ and CD8+ T cell responses for multiple viral and tumor antigens. Interestingly, early exposure of monocytes to high concentrations of IFN-gamma promotes monocyte differentiation into macrophages, despite the presence of GM-CSF and IL-4. However, under low concentrations of IFN-gamma, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-gamma and an inability to generate effective antigen-specific CD4+ and CD8+ T cell responses compared to standard moDCs. Monocytes differentiated in the presence of low levels of IFN-gamma downregulate IFN-gamma receptor expression, impairing their response to an inflammatory rechallenge. These findings demonstrate the ability of IFN-gamma to impart differential programs on human moDCs which shape the antigen-specific T cell responses they induce. Timing and intensity of exposure to IFN-gamma can thus determine whether moDCs are tolerogenic or immunostimulating. Human monocyte-derived dendritic cells from 4 healthy donors were differentiated with either GM-CSF and IL-4 (n=4) or GM-CSF, IL-4, and IFN-gamma (n=4). These samples were subsequently hybridized to arrays as 4 biological repeats for each of the two treatment conditions.

2014-06-01 | E-GEOD-47621 | biostudies-arrayexpress

RNA-Seq to investigate the effect of small molecular compounds on the maturation capacity of monocyte-derived dendritic cells

Project description:Modulating beta-catenin signaling has attractive therapeutic potential in cancer immunotherapy. Various studies have found that beta-catenin can mediate immune evasion in cancer and promote anti-inflammatory features of antigen-presenting dendritic cells. Multiple small-molecule compounds that inhibit Wnt/beta-catenin signaling are currently in clinical development, but none have reached routine clinical use. Thus, new inhibitors of beta-catenin signaling are desirable. This dataset is the result of an investigation of the effect of small molecular compounds axitinib, ICG-001, nitazoxanide, orlistat, and XAV-939 on the maturation capacity of monocyte-derived dendritic cells (moDC). Treatment of immature moDC was done in combination with the beta-catenin activator 6-BIO. Immature moDCs were obtained by isolating monocytes from PBMC using magnetic beads, which were then differentiated into moDCs using GM-CSF and IL-4 for four days. Compounds were added during the maturation of the moDCs, which was done by adding LPS to the cell culture. After the maturation period of 24 hours, the mature moDCs were collected and processed for RNA sequencing.

2021-08-06 | E-MTAB-10757 | biostudies-arrayexpress

GM-CSF Production by Non-Classical Monocytes Controls Antagonistic LPS-driven Functions In Allergic Inflammation

Project description:Lipopolysaccharide (LPS) can either promote or prevent T helper-2 (Th2) cell-allergic responses. However, the underlying mechanism remains unknown. We show here that LPS activity switches from pro-pathogenic to protective depending on the production of GM-CSF by non-classical monocytes. In the absence of GM-CSF, LPS can favor pathogenic Th2 cell responses by supporting the trafficking of lung migratory dendritic cells (mDC2s) into the lung-draining lymph node. However, when non-classical monocytes produce GM-CSF, LPS and GM-CSF synergize to differentiate monocyte-derived DCs (moDCs) that instruct mDC2s for Th2 cell suppression. Importantly, only allergens with cysteine protease activity trigger GM-CSF production by non-classical monocytes. Hence, the therapeutic effect of LPS is restricted to allergens with this enzymatic activity. Treatment with GM-CSF, however, restores the protective effects of LPS. Thus, GM-CSF produced by non-classical monocytes acts as a rheostat that fine-tunes the pathogenic and therapeutic functions of LPS.

2021-12-06 | GSE186449 | GEO

STAT5 tetramerization is a central determinant of monocyte fate and colonic pathogenicity

Project description:In response to external stimuli during immune responses, monocytes can have multifaceted roles such as pathogen clearance and tissue repair. However, aberrant control of monocyte activation can result in chronic inflammation and subsequent tissue damage. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces monocyte differentiation into a heterogenous population of monocyte-derived dendritic cells (moDCs) and macrophages. However, the downstream molecular signals that dictate the differentiation of monocytes under pathological conditions is incompletely understood. We report here that the GM-CSF-induced STAT5 tetramerization is a critical determinate of monocyte fate and function. Monocytes require STAT5 tetramers to differentiate into moDCs, whereas STAT5 tetramer deficiency yields a macrophage phenotype. In the dextran sulfate sodium model of colitis, STAT5 tetramer-deficient monocytes exacerbate disease severity. Mechanistically, GM-CSF signaling in STAT5 tetramer-deficient monocytes results in the overexpression arginase I and a reduction in nitric oxide synthesis following stimulation with lipopolysaccharide. Correspondingly, the inhibition of arginase I activity and supplementation with a sustained concentration of nitric oxide ameliorates the worsened colitis in STAT5 tetramer-deficient mice. Thus, this study suggests a protective role of STAT5 tetramers in inflammatory bowel disease through the regulation of arginine metabolism. We previously reported that STAT5 tetramerization in monocytes is detrimental in autoimmune-mediated neuroinflammation. This study highlights the opposing role of STAT5 tetramers in inflammatory bowel disease.

2023-04-11 | GSE207676 | GEO

The miR-424(322)/503 gene cluster regulates pro- vs anti-inflammatory skin DC subset differentiation by modulating TGF-βsignaling

Project description:TGF-β family ligands are key regulators of dendritic cell (DC) differentiation and activation. Epidermal Langerhans cells (LCs) require TGF-β family signaling for their differentiation and canonical TGF-β1 signaling secures a non-activated LC state. LCs reportedly control skin inflammation and are replenished from peripheral blood monocytes, which also give rise to pro-inflammatory monocyte-derived DCs (moDCs). By studying mechanisms in inflammation, we previously screened LCs vs moDCs for differentially expressed miRNAs. miR-424/503 was the most strongly inversely regulated (moDCs > LCs). We found that miR-424/503 is induced during moDC differentiation and promotes moDC differentiation in human and mouse. Inversely, forced repression of miR-424 during moDC differentiation facilitated TGF-β1-dependent LC differentiation. Mechanistically, miR-424/503 deficiency in monocyte/DC precursors leads to the induction of TGF-β1-response genes critical for LC differentiation. Therefore, the miR-424/503 gene cluster plays a decisive role in anti-inflammatory LC vs pro-inflammatory moDC differentiation from monocytes.

2021-03-27 | GSE169717 | GEO

Gene profile of human CD14+ monocytes and monocyte-derived macrophages

Project description:Comparison of the transcriptome of CD14+ human monocytes and CD14+ human monocyte-derived macrophages generated in the presence of M-CSF (M-MØ) or GM-CSF (GM-MØ).

2022-03-24 | GSE188278 | GEO

Expression data measured by Nanostring of monocyte-derived dendritic cells from healthy individuals stimulated with LPS, influenza, or IFN-beta, or left unstimulated

Project description:Variation in individuals' responses to environmental factors is believed to influence susceptibility to complex diseases in humans. The genetic basis of such variation is poorly understood. We measured gene expression from resting and stimulated dendritic cells (DCs) derived from the peripheral blood of healthy individuals. We stimulated the primary DCs with E. coli lipopolysaccharide (LPS), influenza virus or the cytokine IFNβ, and associated genetic variation between individuals with the observed variation in gene expression and gene induction. We collected peripheral blood from each human donor. We isolated peripheral blood mononuclear cells by Ficoll, and magnetically sorted them for CD14+CD16- monocytes. We then differentiated the monocytes into monocyte-derived dendritic cells (MoDCs) by culturing the cells for 7 days with GM-CSF and IL-4. We stimulated the cells with E. coli lipopolysaccharide (LPS) for 2.5 hr or 5 hr, influenza (PR8 dNS1) for 10 hr, or recombinant IFN-beta for 6.5 hr. Finally, we lysed the cells and ran Nanostring on the lysates.

2014-03-01 | E-GEOD-53165 | biostudies-arrayexpress

RNA sequencing of CD45-negative cells isolated from CNS and lung of GM-CSFind x CD4-CreERT2 and control mice

Project description:Elevated frequencies of GM-CSF-producing helper T (TH) cells are consistently found in multiple sclerosis (MS) patients and GM-CSF expression is a non-redundant feature of pathogenic TH cells in preclinical models of MS. GM-CSF activates an inflammatory signature in monocytes, and their progeny are the most abundant cellular infiltrate in acute MS lesions. To model deregulated GM-CSF levels, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral TH cells. This antigen-independent GM-CSF release induced severe neurological deficits with almost 100% penetrance, accompanied by the infiltration of inflammatory monocyte-derived myeloid cells into the brain stem and spinal cord. Other organs did not show obvious signs for clinical pathology, despite also being infiltrated by inflammatory myeloid cells. We aim to unravel differences between organs, their responses by sequencing CD45-negative tissue cells isolate from the CNS and the lung.

2017-02-21 | E-MTAB-5414 | biostudies-arrayexpress

Differential analysis of GM-CSF-induced inflammatory monocyte-derived cells (MCs) isolated from various organs

Project description:Elevated frequencies of GM-CSF-producing helper T (TH) cells are consistently found in multiple sclerosis (MS) patients and GM-CSF expression is a non-redundant feature of pathogenic TH cells in preclinical models of MS. GM-CSF activates an inflammatory signature in monocytes, and their progeny are the most abundant cellular infiltrate in acute MS lesions. To model deregulated GM-CSF levels, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral TH cells. This antigen-independent GM-CSF release induced severe neurological deficits with almost 100% penetrance, accompanied by the infiltration of inflammatory monocyte-derived myeloid cells into the brain stem and spinal cord. Other organs did not show obvious signs for clinical pathology, despite also being infiltrated by inflammatory myeloid cells. We aim to unravel differences between organs, their responses and also the potential of tissue destruction by infiltrating cells by sequencing inflammatory myeloid cells isolate from the individual organs.

2017-02-21 | E-MTAB-5412 | biostudies-arrayexpress

High-Yield Monocyte, Macrophage, and Dendritic Cell Differentiation from Induced Pluripotent Stem Cells

Project description:Differentiation of induced pluripotent stem cells (iPSC) into monocytes, monocyte-derived macrophages (MDM), and monocyte-derived dendritic cells (moDC) represents a powerful tool for studying human innate immunology and developing novel iPSC-derived immune therapies. Challenges include inefficiencies in iPSC-derived cell cultures, labor-intensive culture conditions, low purity of desired cell types, and feeder cell requirements. Here, a highly efficient method for differentiating monocytes, MDMs, and moDCs that overcomes these challenges is described. The process utilizes commercially-available materials to derive CD34+ progenitor cells that are apically released from a hemogenic adherent fraction (HAF). Subsequently, the HAF gives rise to highly pure (>95%), CD34-CD14+ monocytes in 19-23 days and yields 13.5-fold more monocytes by day 35 when compared to previous methods. These iPSC-monocytes are analogous to human blood-derived monocytes and readily differentiate into MDM and moDC. The efficient workflow and increase in monocyte output heightens feasibility for high throughput studies and enables clinical-scale iPSC-derived manufacturing processes.

2022-06-21 | GSE206201 | GEO

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