ArticleGastroenterology2014
Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis.
Article in Gastroenterology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 2 of them syntheses that pooled it.
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Who cites it
50 citing papers in PubMed, 2 syntheses or guidelines pooled it, 104 citations in OpenAlex.
- Immune Activation in Primary Sclerosing Cholangitis: A Systematic Review and Comparative Analysis With Inflammatory Bowel Diseases.United European gastroenterology journal · 2025Pooled it
- Serum vitamins and homocysteine levels in autoimmune liver disease: A systematic review and meta-analysis.Immunity, inflammation and disease · 2024Pooled it
- Intrahepatic T cell analysis reveals Th17 and MAIT17 enrichment in primary sclerosing cholangitis.JHEP reports : innovation in hepatology · 2026Article
- Vitamin D supplementation is associated with reduced risk of hepatobiliary malignancy in patients with primary sclerosing cholangitis.Hepatology communications · 2026Article
- Beyond bones: Revisiting the role of vitamin D in chronic liver disease.World journal of hepatology · 2025Review
- Bile acids engage the SIPR-STAT3 signaling axis to modulate regulatory T cell responses in fibrosing cholangiopathies.Journal of hepatology · 2025Article
- Central role for cholangiocyte pathobiology in cholestatic liver diseases.Hepatology (Baltimore, Md.) · 2025Review
- T and B cell responses against Epstein-Barr virus in primary sclerosing cholangitis.Nature medicine · 2025Article
- Dissecting the genetic basis and mechanisms underlying the associations between multiple extrahepatic factors and autoimmune liver diseases.Journal of translational autoimmunity · 2025Article
- Intergenic risk variant rs56258221 skews the fate of naive CD4Cell reports. Medicine · 2024Article
- Article
- A protective effect of inflammatory bowel disease on the severity of sclerosing cholangitis.Frontiers in immunology · 2024Article
- Lipid metabolic reprogramming of hepatic CD4Microbiology spectrum · 2023Article
- Inflammasome and pyroptosis in autoimmune liver diseases.Frontiers in immunology · 2023Review
- Farnesoid X receptor antagonizes macrophage-dependent licensing of effector T lymphocytes and progression of sclerosing cholangitis.Science translational medicine · 2022Article
- Unraveling the Complexity of Liver Disease One Cell at a Time.Seminars in liver disease · 2022Review
- Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis.Hepatology (Baltimore, Md.) · 2022Article
- Association between serum 25-hydroxyvitamin d and myeloperoxidase: A cross-sectional study of a general population in China.Frontiers in nutrition · 2022Article
- Immunosenescence: an unexplored role in glomerulonephritis.Clinical & translational immunology · 2022Review
- Gene Set Enrichment Analysis Detected Immune Cell-Related Pathways Associated with Primary Sclerosing Cholangitis.BioMed research international · 2022Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsT-cell-mediated biliary injury is a feature of primary sclerosing cholangitis (PSC). We studied the roles of CD28(-) T cells in PSC and their regulation by vitamin D.
methodsPeripheral and liver-infiltrating mononuclear cells were isolated from blood or fresh liver tissue. We analyzed numbers, phenotypes, functions, and localization patterns of CD28(-) T cells, along with their ability to activate biliary epithelial cells. We measured levels of tumor necrosis factor (TNF)α in liver tissues from patients with PSC and the effects of exposure to active vitamin D (1,25[OH]2D3) on expression of CD28.
resultsA significantly greater proportion of CD4(+) and CD8(+) T cells that infiltrated liver tissues of patients with PSC were CD28(-), compared with control liver tissue (CD4(+): 30.3% vs 2.5%, P < .0001; and CD8(+): 68.5% vs 31.9%, P < .05). The mean percentage of CD4(+)CD28(-) T cells in liver tissues from patients with PSC was significantly higher than from patients with primary biliary cirrhosis or nonalcoholic steatohepatitis (P < .05). CD28(-) T cells were activated CD69(+)CD45RA(-) C-C chemokine receptor (CCR)7(-) effector memory and perforin(+) granzyme B(+) cytotoxic cells, which express CD11a, CX3CR1, C-X3-C motif receptor 6 (CXCR6), and CCR10-consistent with their infiltration of liver and localization around bile ducts. Compared with CD28(+) T cells, activated CD28(-) T cells produced significantly higher levels of interferon γ and TNFα (P < .05), and induced up-regulation of intercellular cell adhesion molecule-1, HLA-DR, and CD40 by primary epithelial cells (3.6-fold, 1.5-fold, and 1.2-fold, respectively). Liver tissue from patients with PSC contained high levels of TNFα; TNFα down-regulated the expression of CD28 by T cells in vitro (P < .01); this effect was prevented by administration of 1,25(OH)2D3 (P < .05).
conclusionsInflammatory CD28(-) T cells accumulate in livers of patients with PSC and localize around bile ducts. The TNFα-rich microenvironment of this tissue promotes inflammation; these effects are reversed by vitamin D in vitro.
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