Senescent Human Liver Endothelial Cells Mediate CD4 ⁺ T Cell Recruitment via ICOSL

ABSTRACT

Senescent cells accumulate in chronically diseased liver tissues and are known to actively contribute to disease pathology. To date, these studies have predominantly focussed on senescence in epithelial cells, such as hepatocytes and biliary epithelial cells, and senescence in liver endothelial cells remains largely understudied. Here, we utilise publicly available single‐cell RNA‐sequencing data, immunohistochemical and immunofluorescent staining to detect senescent endothelial cells within chronically diseased human liver tissues. Next, we develop a novel protocol for the induction of paracrine senescence in primary human liver endothelial cells and explore their functionality. We demonstrate that senescent liver endothelial cells exhibit a reduced scavenging capacity but are still able to support lymphocyte recruitment under physiological flow conditions in vitro. Mechanistically, we determine that inducible T cell costimulator ligand (ICOSL) is an important factor in the specific recruitment of CD4 ⁺ T cells, but antibody blockade, genetic knockdown and genetic overexpression of ICOSL in endothelial cells has no effect on CD8 ⁺ T cell recruitment. Finally, we show that ICOSL gene expression is upregulated in chronically diseased tissues, present in scar‐associated endothelial cells and correlates to CD4 ⁺ T cell infiltration. This is the first study to demonstrate that senescent human liver endothelial cells can potentially shape the liver immune microenvironment in chronic liver disease. Targeting senescent endothelial cells could present new therapeutic opportunities to treat chronic liver diseases.