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

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

PROVIDER: PRJNA1006041 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25658500_1.fastq.gz	Fastqsanger.gz
	SRR25658500_2.fastq.gz	Fastqsanger.gz
	SRR25658501_1.fastq.gz	Fastqsanger.gz
	SRR25658501_2.fastq.gz	Fastqsanger.gz
	SRR25658502_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2023-09-05 | GSE241014 | GEO

Targeting pathogenic CD8<sup>+</sup> tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis.

Project description:Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

| S-EPMC10997620 | biostudies-literature

Bottom-up Proteomics of Saliva in Autoimmune Hepatitis and Primary Biliary Cholangitis

Project description:Autoimmune Hepatitis (AIH) and Primary Biliary Cholangitis (PBC) are autoimmune diseases that target the liver in which the immune system produces an inappropriate response to self-antigens resulting in inflammation, damage, and dysfunction of hepatic tissues. Despite progress in the understanding of the etiopathogenesis and in the diagnostic and therapeutic approach of these diseases, critical issues remain concerning the early diagnosis of affected individuals. The present study aims to detect and characterize by a gel-based bottom-up proteomic approach the acid-insoluble fraction of salivary proteome from patients affected by AIH and PBC with respect to healthy controls (HCs). The study was performed on the salivary acid-insoluble proteins after in-gel digestion starting from: i) the entire SDS-PAGE lane; ii) a portion of the SDS-PAGE at lowest molecular weight (MW </= 25 kDa).

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Project description:Macrophages are critical regulators of immune responses, and link innate immunity to acquired immunity. The precise mechanism of the pathogenesis of autoimmune diseases through tissue-resident macrophage is unclear. The role of the tissue-resident macrophages in the onset or development of autoimmunity was investigated using a murine model for Sjögren’s syndrome.

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Resident macrophage enhances an autoimmune lesion in Sjögren's syndrome

Project description:Resident macrophage enhances an autoimmune lesion in Sjögren's syndrome

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Project description:Primary sclerosing cholangitis (PSC) is an autoimmune-like disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with both PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single cell transcriptomics, and T- and B-cell receptor repertoire analysis of right colon tissue from PSC, IBD, and healthy controls we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia specifically in patients with PSC. This inflammatory signature is characterized by antigen-driven IL-17A+ Foxp3+ CD4 T-cell and an expansion of IgG-secreting B-cell responses. These data results suggest that the mechanisms that drive the emergence of dysplasia in of PSC and IBD dysplasia are distinct and provide molecular insights to guide prevention of colorectal cancer in PSC.

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Antigen-driven colonic inflammation is associated with development of dysplasia in primary sclerosing cholangitis [bulk RNASeq]

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

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