颗粒酶B
细胞毒性T细胞
颗粒酶
颗粒酶A
免疫学
穿孔素
医学
免疫系统
化学
T细胞
CD8型
体外
生物化学
作者
Mareike Kellerer,Sana Javed,Christian Casar,Nathan Will,L Berkhout,Dorothee Schwinge,Christian Krebs,Christoph Schramm,Katrin Neumann,Gisa Tiegs
标识
DOI:10.1097/hep.0000000000000830
摘要
Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis. We showed an elevated interferon (IFN)γ response in PSC patients and in multidrug resistance protein 2-deficient ( Mdr2 -/- ) mice developing sclerosing cholangitis. Interferon (IFN)γ induced expression of the cytotoxic molecules granzyme B (GzmB) and TNF-related apoptosis-inducing ligand (TRAIL) in hepatic lymphocytes and mediated liver fibrosis in sclerosing cholangitis. Approach & Results: In patient samples and Mdr2 -/- mice, we identified lymphocyte clusters with a cytotoxic gene expression profile using single-cell RNA-seq and CITE-seq analyses combined with multi-parameter flow cytometry. CD8 + T cells and NK cells showed increased expression of GzmB and TRAIL in sclerosing cholangitis. Depletion of CD8 + T cells ameliorated disease severity in Mdr2 -/- mice. By using Mdr2 -/- x Gzmb -/- and Mdr2 -/- x Tnfsf10 -/- mice, we investigated the significance of GzmB and TRAIL for disease progression in sclerosing cholangitis. Interestingly, lack of GzmB resulted in reduced cholangiocyte apoptosis, liver injury and fibrosis. In contrast, sclerosing cholangitis was aggravated in absence of TRAIL. This correlated with elevated GzmB and IFNγ expression by CD8 + T cells and NK cells, enhanced T-cell survival and increased apoptosis and expansion of cholangiocytes. Conclusion: GzmB induces apoptosis and fibrosis in sclerosing cholangitis, whereas TRAIL regulates inflammatory and cytotoxic immune responses subsequently leading to reduced liver injury and fibrosis.
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