??T Cells Suppress Liver Fibrosis via Strong Cytolysis and Enhanced NK Cell-Mediated Cytotoxicity Against Hepatic Stellate Cells.

ABSTRACT: Liver fibrosis is the excessive accumulation of extracellular matrix proteins, resulting from maladaptive wound healing responses to chronic liver injury. ??T 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 ??T cells contribute to liver fibrosis regression. Using a carbon tetrachloride (CCl4)-induced murine model of liver fibrosis in wild-type (WT) and ??T cell deficient (TCR?-/-) mice, we demonstrated that ??T cells protected against liver fibrosis and exhibited strong cytotoxicity against activated hepatic stellate cells (HSCs). Further study show that chronic liver inflammation promoted hepatic ??T cells to express NKp46, which contribute to the direct killing of activated HSCs by ??T cells. Moreover, we identified that an IFN?-producing ??T cell subset (??T1) cells exhibited stronger cytotoxicity against activated HSCs than the IL-17-producing subset (??T17) cells upon chronic liver injury. In addition, ??T 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 ??T 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 ??T cells, especially the ??T1 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.

SUBMITTER: Liu M 

PROVIDER: S-EPMC6428727 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature