CD8 + tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells.

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8 ⁺ tissue-resident memory CD8 ⁺ T (CD8 ⁺ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69 ⁺ CD103 ^- CD8 ⁺ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8 ⁺ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8 ⁺ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69 ⁺ CD8 ⁺ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8 ⁺ Trm in fibrosis resolution.
(© 2021. The Author(s).)