Dataset Information

Imbalance of the CD226/TIGIT Immune Checkpoint Is Involved in the Pathogenesis of Primary Biliary Cholangitis.

ABSTRACT: The relationship between the cluster of differentiation 226 (CD226)/T cell Ig and ITIM domain (TIGIT) immune checkpoint and primary biliary cholangitis (PBC) pathogenesis is unknown. Herein, PBC patients (n = 42) showed significantly higher proportions of peripheral CD8+ T and CD4+ T cells expressing either CD226 or TIGIT than disease (n = 25) and healthy (n = 30) controls. The percentage of CD8+TIGIT+ T cell was negatively associated with total bilirubin, direct bilirubin, total bile acid, ?-glutamyl transpeptidase, and alkaline phosphatase, but positively correlated with platelet count; alkaline phosphatase was positively associated with the frequency of CD8+CD226+ T cell; and the CD226/TIGIT ratio of CD8+ T cell was positively associated with total bilirubin, direct bilirubin, total bile acid, ?-glutamyl transpeptidase, alkaline phosphatase, and aspartate aminotransferase to platelet ratio, but negatively correlated with albumin and platelet count. The effector function of CD8+CD226+ T cells was more robust than the CD8+CD226- counterparts. CD226 blockade reduced CD107a+, IFN-?+, and TNF-?+ proportions among CD8+CD226+ T cells, inhibiting CD8+ T cell proliferation. In conclusion, CD226/TIGIT immune checkpoint imbalance is involved in the pathogenesis of PBC. The CD226/TIGIT ratio of CD8+ T cell is a potential biomarker for evaluating the disease status and the prognosis of PBC patients. Moreover, CD8+CD226+ T cells represent a possible therapeutic target for PBC, and blocking CD226 could inhibit the activity of this cell subset in vitro.

SUBMITTER: Deng C

PROVIDER: S-EPMC7393007 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Imbalance of the CD226/TIGIT Immune Checkpoint Is Involved in the Pathogenesis of Primary Biliary Cholangitis.

Deng Chuiwen C Li Wenli W Fei Yunyun Y Wang Li L Chen Yingying Y Zeng Xiaofeng X Zhang Fengchun F Li Yongzhe Y

Frontiers in immunology 20200724

The relationship between the cluster of differentiation 226 (CD226)/T cell Ig and ITIM domain (TIGIT) immune checkpoint and primary biliary cholangitis (PBC) pathogenesis is unknown. Herein, PBC patients (n = 42) showed significantly higher proportions of peripheral CD8+ T and CD4+ T cells expressing either CD226 or TIGIT than disease (n = 25) and healthy (n = 30) controls. The percentage of CD8+TIGIT+ T cell was negatively associa ...[more]

PMID: 32793241

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Project description:Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although its etiopathogenesis remains obscure, development of antimitochondrial autoantibodies against pyruvate dehydrogenase complex E2 is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but its functional relevance is largely unknown. We previously reported that miR-506 is overexpressed in PBC cholangiocytes and directly targets both Cl- / HCO3- anion exchanger 2 and type III inositol 1,4,5-trisphosphate receptor, leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several proinflammatory cytokines overexpressed in PBC livers (such as interleukin-8 [IL8], IL12, IL17, IL18, and tumor necrosis factor alpha) stimulated miR-506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR-506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR-506 (1) induced dedifferentiation with down-regulation of biliary and epithelial markers together with up-regulation of mesenchymal, proinflammatory, and profibrotic markers; (2) impaired cell proliferation and adhesion; (3) increased oxidative and endoplasmic reticulum stress; (4) caused DNA damage; and (5) sensitized to caspase-3-dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less adenosine triphosphate production) and pyruvate dehydrogenase complex E2 overexpression. Coculture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. CONCLUSION:Different proinflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells; miR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients. (Hepatology 2018;67:1420-1440).

Dataset Information

Imbalance of the CD226/TIGIT Immune Checkpoint Is Involved in the Pathogenesis of Primary Biliary Cholangitis.

Publications

Imbalance of the CD226/TIGIT Immune Checkpoint Is Involved in the Pathogenesis of Primary Biliary Cholangitis.

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