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

Yuzo Koda, Toshiaki Teratani, Po Sung Chu, Yuya Hagihara, Yohei Mikami, Yosuke Harada, Hanako Tsujikawa, Kentaro Miyamoto, Takahiro Suzuki, Nobuhito Taniki, Tomohisa Sujino, Michiie Sakamoto, Takanori Kanai, Nobuhiro Nakamoto

Research output: Contribution to journalArticlepeer-review

Abstract

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+CD103CD8+ 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.

Original languageEnglish
Article number4474
JournalNature communications
Volume12
Issue number1
DOIs
Publication statusPublished - 2021 Dec

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'CD8<sup>+</sup> tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells'. Together they form a unique fingerprint.

Cite this