LXR signaling controls homeostatic dendritic cell maturation [BulkRNAseq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA950098 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24009600.fastq.gz | Fastqsanger.gz | |||
| SRR24009601.fastq.gz | Fastqsanger.gz | |||
| SRR24009602.fastq.gz | Fastqsanger.gz | |||
| SRR24009603.fastq.gz | Fastqsanger.gz | |||
| SRR24009604.fastq.gz | Fastqsanger.gz |
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Project description:Depending on how an antigen is perceived, dendritic cells (DCs) mature in an immunogenic or tolerogenic manner, safeguarding the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well characterized, the signals driving tolerogenic maturation in homeostasis are still poorly understood. Here we demonstrate that engulfment of apoptotic cells triggers homeostatic maturation of conventional cDC1s in the spleen. This process can be modeled by engulfment of empty, non-adjuvanted lipid nanoparticles (LNPs), is marked by intracellular accumulation of cholesterol, and highly unique to type 1 DCs. Engulfment of apoptotic cells or cholesterol-rich LNPs leads to activation of the LXR pathway driving cellular cholesterol efflux and repression of immunogenic genes. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs represses the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell immunity. These data demonstrate how DCs exploit the conserved cellular cholesterol efflux pathway to regulate induction of tolerance or immunity and reveal that administration of non-adjuvanted cholesterol-rich LNPs is a powerful platform for inducing tolerogenic DC maturation.
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Project description:LXR signaling controls homeostatic dendritic cell maturation
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Project description:Depending on how an antigen is perceived, dendritic cells (DCs) mature in an immunogenic or tolerogenic manner, safeguarding the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well characterized, the signals driving tolerogenic maturation in homeostasis are still poorly understood. Here we demonstrate that engulfment of apoptotic cells triggers homeostatic maturation of conventional cDC1s in the spleen. This process can be modeled by engulfment of empty, non-adjuvanted lipid nanoparticles (LNPs), is marked by intracellular accumulation of cholesterol, and highly unique to type 1 DCs. Engulfment of apoptotic cells or cholesterol-rich LNPs leads to activation of the LXR pathway driving cellular cholesterol efflux and repression of immunogenic genes. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs represses the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell immunity. These data demonstrate how DCs exploit the conserved cellular cholesterol efflux pathway to regulate induction of tolerance or immunity and reveal that administration of non-adjuvanted cholesterol-rich LNPs is a powerful platform for inducing tolerogenic DC maturation.
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Project description:Dendritic cells (DCs) play a crucial role in the regulation of innate and adaptive immune responses. DCs initiate adaptive immune responses after their migration to secondary lymphoid organs, a process mainly driven by the expression of the chemokine receptor CCR7. LXR ligands/oxysterols released by tumors were shown to dampen DC migration to secondary lymphoid organs by the inhibition of CCR7 expression. We studied the gene expression modulation of DCs undergoing maturation (by LPS) in the presence of the oxysterol 22R-Hydroxycholesterol (22R-HC).
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:XCR1+ dendritic cells (DC) have been shown to excel in antigen cross-presentation for the activation of naïve CD8 T cells. This property was reported to be associated to the subset of the XCR1+ DC expressing IL-12b upon ex vivo stimulation for 24 h with a mixture of CpG, IFN-γ, and GM-CSF (Lin ML et al. Proc Natl Acad Sci USA. 2008. PMID: 18272486). DC found in the steady-state non-lymphoid tissues undergo an homeostatic, tolerogenic, maturation and migrate to the draining lymph nodes to interact with naive autoreactive T cells and induction their peripheral tolerance. In contrast, spleen DC are thought to exist solely in an immature state. The aim of this study was to re-examine heterogeneity within steady state spleen XCR1+ DC, in particular examining whether this population encompass a fraction of mature DCs as assessed through their expression of CCR7 and/or the Il12b gene. Indeed, we show that a small fraction of XCR1+ spleen DC constitutively mature into two distinct but likely successive activation stages characterized as CCR7+ and CCR7+Il12b+ respectively, and correlated with increasing ability to cross-present antigen to naïve CD8 T cells. Transcriptomic analysis of the subsets of XCR1+ DC found in steady state spleen unexpectedly showed that their homeostatic maturation was unexpectedly associated with up-regulated of many genes thought to drive pro-inflammatory T-cell responses and previously found to be commonly induced upon maturation of distinct DC subsets in response to stimulation by various microbial-type stimuli (Vu Manh TP et al. Eur J Immunol. 2013. PMID: 23553052). Thus, our results reveal that spleen XCR1+ DC undergo constitutive maturation and emphasize the common mechanisms operating upon homeostatic, tolerogenic, DC maturation versus microbial-type stimuli-induced, immunogenic, DC maturation. DC were isolated from the spleen of untreated Il12b-EYFP reporter mice (Reinhardt RL et al. J Immunol. 2006. PMID:16849470) mice as previously described (Robbins SH et al. Genome Biol. 2008. PMID: 18218067; Baranek T et al. Cell Host Microbe. 2012. PMID: 23084923). DC subsets were sorted by flow cytometry according to the marker combinations described in the âcharacteristics: phenotypeâ field for each sample.
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