Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Engineered probiotics limit T-cell driven CNS autoimmunity by activating AHR-KLF4-FADS3 signaling in intestinal dendritic cells

ABSTRACT: Dendritic cells (DCs) control the induction of effector immune responses and tolerance. The development and function of DCs is regulated by transcriptional, epigenetic and metabolic programs, but the mechanisms controlling DC metabolism and its impact on autoimmune diseases remain poorly understood. Here, using single-cell and bulk RNA-sequencing, in vivo DC-specific gene perturbations, multiple sclerosis (MS) clinical samples and preclinical models, we identified an aryl hydrocarbon receptor (AHR) - Krüppel-like factor 4 (KLF4) - fatty acid desaturase enzyme 3 (FADS3) axis which drives the production of docosahexaenoic acid (DHA) in DCs and limits effector T-cell responses and the development of experimental autoimmune encephalomyelitis (EAE). Furthermore, we used synthetic biology approaches to engineer a probiotic (EcNIAA) that produces the AHR agonist indole-3-acetic acid (IAA) as a tool to limit pathogenic inflammatory responses. EcNIAA administration activates AHR-KLF4-FADS3 signaling in intestinal DCs, increasing DHA production and suppressing encephalitogenic T cells that originate in the gut and migrate to the central nervous system to promote autoimmune pathology. Briefly, we identified a novel immunometabolic axis that operates in DCs to limit effector T-cell responses, and can be targeted with engineered probiotics to treat autoimmunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE296433 | GEO | 2026/05/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other
	GSE296433_RAW.tar	Raw
	filelist.txt	Txt

Items per page:

1 - 3 of 3

Similar Datasets

Anti-TIM3-IFN fusion protein rejuvenates tumor-infiltrating exhausted TIM3+CD8+ T cells through activating intratumoral dendritic cells

Project description:While tumor-infiltrating T cells are central to tumor regression, their function is progressively compromised by the exhaustive conditions of the tumor microenvironment. The capacity of intratumoral dendritic cells (DCs) to mitigate this exhaustion state is not fully understood. Here, we investigate a therapeutic strategy that leverages a bispecific DC-T cell engager (BiDT), constructed from anti-TIM3 and IFNα, to simultaneously targeting TIM3 on exhausted TILs and the IFNAR receptor on DCs. Through transcriptional profiling, we elucidate the mechanism by which BiDT operates: it concurrently targets TIM3+ TILs and IFNAR+ DCs, triggering a reprogramming of the local immune repertoire. Mechanistic analysis indicates that BiDT rescues T cells from apoptosis by enhancing Bcl2 expression and restores their effector functions. Crucially, the data uncovers a reciprocal activation loop wherein BiDT-stimulated DCs further potentiate T cell responses via IL-2 and B7/CD28 signaling pathways. We further validated an engineered Pro-BiDT variant designed to limit systemic toxicity. These results underscore the importance of re-establishing functional DC-T cell circuitry as a viable strategy to enhance anti-tumor immunity.

2026-02-24 | GSE320312 | GEO

Effect of free D-Lactate in CNS pathology

Project description:Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1a. NDUFA4L2 promotes mitochondrial fitness in DCs, limiting the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1a/NDUFA4L2 signaling in DCs. In summary, we identified a novel immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation via the gut-brain axis.

2023-08-18 | GSE188500 | GEO

Effect of XBP1-deficiency in DCs on CNS pathology

2023-08-18 | GSE188502 | GEO

Analyses of HIF-1a-deficient DCs in the context of pre-clinical model of Multiple Sclerosis, Experimental Autoimmune Encephalomielitis (EAE)

2023-08-18 | GSE188499 | GEO

Study of the protective effect of D-Lactate-producing probiotics on CNS pathology

2023-08-18 | GSE188503 | GEO

Dendritic cells regulate the innate-adaptive balance in lymph nodes for optimal host defense

Project description:Lymph nodes (LNs) enable innate defense to limit pathogen dissemination while also driving adaptive immunity. Yet, certain innate responses can restrict adaptive processes, suggesting that these must be tightly regulated. Here, we report that after infection or immunization, LN architecture is rapidly altered, with large-scale, polarized recruitment of neutrophils and monocytes from inflamed blood vessels, and intranodal repositioning of NK cells. Mechanistically, dendritic cells (DCs) promote this process through expression of inflammatory chemokines and integrin ligands. While necessary for efficient pathogen containment, DC-driven innate cell responses paradoxically limit early adaptive immunity, with infiltrating neutrophils displacing lymphocytes and reducing the LN area available for T cell priming. Upon threat secession however, DCs and DC-recruited monocytes phagocytose the neutrophils, restoring tissue architecture and generating polarized domains for downstream adaptive immune cell activation. Thus, DCs orchestrate innate cell organization during inflammation, serving as rheostats of innate versus adaptive functions of the LN.

2025-02-03 | GSE288378 | GEO

HERPES SIMPLEX VIRUS TYPE 1 IMPAIRS DENDRITIC CELL FUNCTION BY REMODELLING NEUTRAL LIPID METABOLISM AND INDUCING LIPID DROPLET ACCUMULATION

Project description:Herpes simplex virus type 1 (HSV-1) infects dendritic cells (DCs), professional antigen-presenting cells that initiate and regulate host antiviral responses. HSV-1 infects DCs limiting their maturation, migration to draining lymph nodes and T cell activation capacity, ultimately promotes their apoptosis. Here, we investigated the impact of HSV-1 infection over neutral lipid metabolism in DCs and their function. We found that HSV-1 significantly alters neutral lipid metabolism in infected DCs and promotes LD accumulation. Pharmacological inhibition of cholesterol ester synthesis, or fatty acid transporter proteins in infected DCs reduced LD accumulation and viral replication, enhanced DC viability and DC migration to draining lymph nodes and promoted DC priming of virus-specific CD8+ T cells. These findings highlight the role of neutral lipid metabolism in HSV-1-infected DCs and its impact over host immunity against this virus, underscoring lipid metabolism in DCs as a potential therapeutical target for triggering antiviral immunity against HSV-1.

2025-04-03 | MTBLS5163 | MetaboLights

AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism

Project description:Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by a several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity, and suggest AMPK as target to direct DC-driven tolerogenic responses in therapeutic settings.

2024-07-16 | PXD053979 | Pride

Pharmacological Targeting of ALDH1a2 in Dendritic Cells Enhances Antigen Presentation, T Cell Activation and Anti-tumor immunity

Project description:Dendritic cell (DC) vaccines have been proposed as cancer immunotherapies due to their role as crucial antigen-presenting cells that regulate T cell functions. Despite considerable efforts to optimize ex vivo priming of DCs, DC vaccines have rarely been successful, suggesting the presence of unknown inhibitory factors. Here, we examined DC differentiation dynamics and discovered that ALDH1a2-produced retinoic acid (RA) acts as a bottleneck factor, initiating negative feedback to inhibit DC maturation. Removing this inhibition through either genetic knockout or pharmacological blockade using KyA33, an ALDH1a2 inhibitor we developed, significantly enhances DC maturation, phagocytosis, antigen presentation, and T cell activation, in part by downregulating glucose metabolism. KyA33 demonstrates favorable drug-like properties, including low toxicity, high membrane permeability, and low cell efflux rate. Its non-covalent binding to ALDH1A2 was also validated through X-ray crystallography. Importantly, application of KyA33 generates more robust DCs vaccines, promoting anti-tumor immunity through enhancing antigen-specific T cell responses. Our investigation highlights the intricate interplay between retinoid signaling, dendritic cell maturation, and immune metabolism, offering promising avenues for enhancing cancer immunotherapies.

2025-12-19 | PXD052724 | Pride

Lymphoid tissue specific homing of bone marrow-derived dendritic cells

Project description:Because of their potent immunoregulatory capacity, dendritic cells (DCs) have been exploited as therapeutic tools to boost immune responses against tumors or pathogens, or dampen autoimmune or allergic responses. Murine bone marrow-derived DCs (BM-DCs) are the closest known equivalent of the blood monocyte-derived DCs that have been used for human therapy. Current imaging methods have proven unable to properly address the migration of injected DCs to small and deep tissues in mice and humans. This study presents the first extensive analysis of BM-DC homing to lymph nodes (and other selected tissues) after intravenous and intraperitoneal inoculation. Following intravenous delivery, DCs accumulated in the spleen, and preferentially in the pancreatic and lung-draining lymph nodes. In contrast, DCs injected intraperitoneally were found predominantly in peritoneal lymph nodes (pancreatic in particular), and in omentum-associated lymphoid tissue. This uneven distribution of BM-DCs, independent of the mouse strain and also observed within pancreatic lymph nodes, resulted in the uneven induction of an immune response in different lymphoid tissues. These data have important implications for the design of systemic cellular therapy with DCs, and in particular underlie a previously unsuspected potential for specific treatment of diseases such as autoimmune diabetes and pancreatic cancer. This SuperSeries is composed of the following subset Series: GSE15748: Gene expression in PLN vs. ILN or MLN in mice GSE15753: Gene expression in GLN versus PDLN in NOD mice Refer to individual Series

2009-04-23 | E-GEOD-15784 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data