Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins, resulting from maladaptive wound healing responses to chronic liver injury. γδT cells are important in chronic liver injury pathogenesis and subsequent liver fibrosis; however, their role and underlying mechanisms are not fully understood. The present study aims to assess whether γδT cells contribute to liver fibrosis regression. Using a carbon tetrachloride (CCl4)-induced murine model of liver fibrosis in wild-type (WT) and γδT cell deficient (TCRδ−/−) mice, we demonstrated that γδT cells protected against liver fibrosis and exhibited strong cytotoxicity against activated hepatic stellate cells (HSCs). Further study show that chronic liver inflammation promoted hepatic γδT cells to express NKp46, which contribute to the direct killing of activated HSCs by γδT cells. Moreover, we identified that an IFNγ-producing γδT cell subset (γδT1) cells exhibited stronger cytotoxicity against activated HSCs than the IL-17-producing subset (γδT17) cells upon chronic liver injury. In addition, γδT cells promoted the anti-fibrotic ability of conventional natural killer (cNK) cells and liver-resident NK (lrNK) cells by enhancing their cytotoxicity against activated HSCs. The cell crosstalk between γδT and NK cells was shown to depend partly on co-stimulatory receptor 4-1BB (CD137) engagement. In conclusion, our data confirmed the protective effects of γδT cells, especially the γδT1 subset, by directly killing activated HSCs and increasing NK cell-mediated cytotoxicity against activated HSCs in CCl4-induced liver fibrosis, which suggest valuable therapeutic targets to treat liver fibrosis.
Highlights
Liver fibrosis is a prevalent liver disease that can lead to cirrhosis and liver failure, accounting for about 45% of deaths in industrialized countries [1]
We found that cotimulatory receptor 4-1BB (CD137) blockade did not impair the direct lytic functions of hepatic conventional natural killer (cNK) and liver-resident NK (lrNK) cells against Hepatic stellate cells (HSCs); in the cNK or lrNK and γδT cell co-culture system, the increased lytic functions of hepatic cNK and lrNK cells against activated HSCs promoted by γδT cells were significantly attenuated in the presence of the CD137Lspecific blocking antibody (Figures 8C,D), which suggested that γδT Cells Suppress Liver Fibrosis
Some studies revealed that γδT cells might inhibit fibrogenesis by inducing apoptosis of activated HSCs in a FasLdependent manner, while others emphasized the pathogenic role of γδT cells through IL-17A-mediated enhancement of HSCs activation in carbon tetrachloride (CCl4)-induced liver injury and liver fibrosis [8, 19, 30]
Summary
Liver fibrosis is a prevalent liver disease that can lead to cirrhosis and liver failure, accounting for about 45% of deaths in industrialized countries [1]. The scar tissue, comprising collagen-rich extracellular matrix, replaces normal functional units of cells, leading to the progressive loss of organ function and eventual failure [2]. Hepatic stellate cells (HSCs) are the main effector cells in liver fibrosis because of their capacity to transdifferentiate into collagen-producing myofibroblasts [3]. HSCs become activated, lose their vitamin A droplets, and transdifferentiate into extracellular matrixproducing myofibroblasts, which promote hepatic fibrosis [4, 5]. Their location in the narrow space of Dissé between hepatocytes and sinusoidal endothelial cells mean that HSCs contact closely with other liver cell types. Certain immune cells interact with HSCs via cell-cell interactions or by secreting soluble mediators, possibly influencing the progress of liver fibrosis [3]
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