CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells.
Yuzo KodaToshiaki TerataniPo-Sung ChuYuya HagiharaYohei MikamiYosuke HaradaHanako TsujikawaKentaro MiyamotoTakahiro SuzukiNobuhito TanikiTomohisa SujinoMichiie SakamotoTakanori KanaiNobuhiro NakamotoPublished in: Nature communications (2021)
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.
Keyphrases
- liver fibrosis
- cell cycle arrest
- induced apoptosis
- single cell
- cell death
- endoplasmic reticulum stress
- single molecule
- oxidative stress
- nk cells
- metabolic syndrome
- type diabetes
- adipose tissue
- immune response
- cell therapy
- signaling pathway
- working memory
- regulatory t cells
- cell proliferation
- insulin resistance
- idiopathic pulmonary fibrosis
- quality improvement