Blood-derived extracellular vesicles of patients with liver cirrhosis and acute-on-chronic liver induce mitochondrial dysfunction in T cells

Background and aims Patients with liver cirrhosis (LC) and acute-on-chronic liver failure (ACLF) show distinct changes regarding the cellular structure of the liver and the immune system. Communication of different liver cell subtypes and immune cells plays an important role during disease development and progression. Extracellular vesicles (EVs) are important in intercellular communication and immune regulation. We therefore aimed to characterize the phenotype and function of EVs of patients with LC with or without ACLF.

Method Patients with compensated or decompensated LC or ACLF were recruited from a prospective cohort study at the University Hospital Essen. Precipitation methods were used to isolate EVs. EVs were characterized regarding particle size, concentration, surface markers and protein content by Nanoparticle Tracking Analysis (NTA), flow cytometry, Western Blot and Mass Spectrometry. Additionally, smallRNA sequencing was performed. Functional analyses were performed to assess the impact of EVs on T cells.

Results EVs derived from 84 LC and ACLF patients show lower expression of exosome-specific markers (e.g. CD9, CD81) and higher levels of liver cell-specific markers (e.g. ASGPR1, CD163) compared to healthy donor EVs. Particle concentration in blood of patients is decreased with disease severity, whereas the average size is increased. In functional assays, blood-derived EVs of LC and - to a stronger extend - of ACLF patients led to changes in the composition of immune cell populations, e.g. by downregulation of CD197 on T cells. In addition, EVs decreased the viability of CD3⁺ T cells, which could be explained by induction of mitochondrial dysfunction in CD4⁺ and CD8⁺ T cells.

Conclusion The phenotype of EVs from patients with LC and ACLF differs significantly from healthy donors. The vesicles show immunomodulatory functions on the CD4⁺ and CD8⁺ T cell compartment, which may be explained by an induction of mitochondrial dysfunction.

Publication History

Article published online:
07 September 2021