Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis

ABSTRACT: Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease secondary to an autoreactive T cell response against intrahepatic small bile ducts. Multiple murine models have demonstrated the critical role of effector CD8+T cells in this response and our work has used IL-12p40-/-IL-2Rα-/- mice (DKO mice) to study this issue. Herein we first demonstrated that use of either a CD8a knock-out or an anti-CD8a antibody prevents/reduces biliary immunopathology. Bulk and single-cell RNA sequencing analysis identifies CD8+ tissue resident memory T cells (Trm) in the liver of DKO mice, which highly express activation and cytotoxicity associated markers and have the ability to induce apoptosis of bile duct epithelial cells. Liver CD8+Trm cells also upregulate expression of several immune checkpoint molecules and in particular we identified PD-1 as a specific liver CD8+Trm cell marker in this model. Based on these data we constructed a novel chimeric antigen receptor containing a PD-L1 extracellular domain to target PD-1-expressing CD8+Trm cells. Importantly, treatment of DKO mice with PD-1 targeting CAR-T cells selectively depleted liver CD8+Trm cells in vivo and alleviated autoimmune cholangitis.

ORGANISM(S): Mus musculus

PROVIDER: GSE241014 | GEO | 2023/09/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

PD-1+CD8+ T Cell-Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver Disease

Project description:The specific mechanisms underlying effector pathways in autoimmune liver disease remain enigmatic and therefore constructing appropriate murine models to investigate disease pathogenesis becomes critical. A spontaneous severe murine model of autoimmune liver disease has been previously established in dnTGFβRII Aire-/- mice, exhibiting disease phenotypes that resemble both human primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). The data suggest that auto-reactive liver-specific CD8+ T cells are the primary pathogenic cells in liver injury. In this study, these data are advanced through the use of both single-cell sequencing and extensive in vitro analysis. The results identify a specific expanded pathogenic subset of PD-1+CD8+ T cells in the liver, exhibiting strong functional activity and cytotoxicity against target cells. Depletion of PD-1+CD8+ T cells using CAR-T cells effectively alleviates the disease. GSDMD-mediated pyroptosis is found to be aberrantly activated in the livers of model mice, and treatment with a GSDMD-specific inhibitor significantly inhibits disease progression. In vitro experiments reveal that PD-1+CD8+ T cells can induce the pyroptosis of hepatocytes through elevated production of granzyme B and perforin-1. These results provide a novel explanation for the cytotoxic activity of pathogenic liver PD-1+CD8+ T cells in autoimmune liver diseases and offer potential therapeutic targets.

2024-10-31 | GSE199065 | GEO

Gut microbiome dysregulation is associated with elevated toxic bile acids in Parkinson’s disease

Project description:The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD) patients. The vermiform appendix is a lymphoid tissue implicated in the storage and regulation of the gut microbiome. Here, we investigate changes in the functional microbiome in the appendix of PD patients relative to controls by metatranscriptomic analysis. In the PD appendix, we find microbial dysbiosis affecting lipid metabolism, particularly an upregulation of bacteria responsible for secondary bile acid synthesis. Likewise, proteomic and transcript analysis in the PD gut corroborates a disruption in cholesterol homeostasis and lipid catabolism. Bile acid analysis in the PD appendix reveals an increase in the microbially-derived, toxic secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA). Synucleinopathy in mice induces similar microbiome alterations to those of PD patients and heightens microbial changes to gut inflammation. As observed in PD, the mouse model of synucleinopathy has elevated DCA and LCA. Raised levels of DCA and LCA can lead to liver injury, and an analysis of blood markers of liver dysfunction shows evidence of biliary abnormalities in PD patients, including elevated alkaline phosphatase and bilirubin. Increased bilirubin levels are also evident before PD diagnosis, in individuals at-risk of developing PD. In sum, microbially-derived toxic bile acids are heightened in PD and biliary changes may even precede the onset of overt motor symptoms.

2021-01-28 | PXD020988 | Pride

Downregulation of TGR5 (GPBAR1) in biliary epithelial cells is characteristic of sclerosing cholangitis and may contribute to disease pathogenesis

Project description:Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5 expression in BECs may contribute to PSC pathogenesis.

2021-03-12 | GSE168758 | GEO

Serum and bile proteomics reveal candidates for new noninvasive serum markers of primary sclerosing cholangitis and of risk of disease progression and biliary neoplasia.

Project description:Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by biliary strictures, cholestasis, and an increased risk of cholangiocarcinoma (CCA). Here, we have used label-free quantitative proteomics to analyze serum and bile samples from non-PSC controls and PSC patients, as well as from PSC patients divided into groups according to endoscopic retrograde cholangiography score (with a score of >4 indicating advanced disease) and presence or absence of biliary dysplasia/CCA. Further analyses subsequently identified multiple candidates of new noninvasive serum markers for the diagnosis of PSC, as well as new markers for the prediction of the risk of disease progression and biliary neoplasia for patients already diagnosed with PSC.

2022-08-03 | PXD026693 | Pride

Serum and bile proteomics reveal candidates for new noninvasive serum markers of primary sclerosing cholangitis and of risk of disease progression and biliary neoplasia (BILE)

2022-08-03 | PXD026694 | Pride

Gut microbiome dysregulation is associated with elevated toxic bile acids in Parkinson’s disease

2021-08-01 | GSE156647 | GEO

Single-cell transcriptome and TCR sequencing reveals immune cell heterogeneity in the submandibular gland of SS mice

Project description:In this study, we analyzed the submandibular gland and submandibular gland-draining lymph nodes of P40-/-CD25-/- (SS mice) and P40-/-CD25+/- (control mice) using single-cell transcriptome and TCR sequencing of leukocytes. A total of 24,115 cells were obtained for analysis, of which 9,897 cells were from the submandibular gland and 14,218 cells were from the draining lymph nodes. We found that tissue-resident CD8+T cells (CD8+Trm) in the submandibular gland of SS mice expanded massively and highly expressed PD-1. These CD8+Trm cells, which highly express PD-1, exhibit clonal expansion and cytotoxicity. In addition, shared TCR analysis found that potential CD8+Trm precursor cells in the draining lymph nodes exhibited a Gzmk+Pdcd1+ phenotype. In summary, we found that PD-1+CD8+Trm cells in the submandibular gland of SS mice are potentially pathogenic and their precursors also express PD-1.

2024-12-15 | GSE253042 | GEO

microRNA profile in CD4+ T cell in healthy control and Primay biliary cholangitis (PBC) [miRNA]

Project description:Primary biliary cholangitis (PBC), formally known as primary biliary cirrhosis, is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. As CD4+ T cells play a pivotal role in immunological dysfunction observed in PBC, we analyzed microRNA(miRNA) and mRNA expression in CD4+ T cells to investigate PBC pathogenesis and identify novel therapeutic targets.

2017-01-06 | GSE93171 | GEO

mRNA profile in CD4+ T cell in healthy control and Primay biliary cholangitis (PBC) [mRNA]

2017-01-06 | GSE93170 | GEO

RNA-sequencing of livers from p40-/-IL-2Rα-/- PBC mouse model and control.

Project description:We performed RNA sequencing of liver transcriptome from 12-week-old p40-/-IL-2Rα-/- (a mouse model of primary biliary cholangitis) and littermate p40-/-IL-2Ra+/- (control) mice.

2021-09-16 | GSE184066 | GEO

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