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 () and Nobuhiro Nakamoto ()
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Yuzo Koda: Keio University School of Medicine
Toshiaki Teratani: Keio University School of Medicine
Po-Sung Chu: Keio University School of Medicine
Yuya Hagihara: Keio University School of Medicine
Yohei Mikami: Keio University School of Medicine
Yosuke Harada: Keio University School of Medicine
Hanako Tsujikawa: Keio University School of Medicine
Kentaro Miyamoto: Keio University School of Medicine
Takahiro Suzuki: Keio University School of Medicine
Nobuhito Taniki: Keio University School of Medicine
Tomohisa Sujino: Keio University School of Medicine
Michiie Sakamoto: Keio University School of Medicine
Takanori Kanai: Keio University School of Medicine
Nobuhiro Nakamoto: Keio University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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+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.

Date: 2021
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DOI: 10.1038/s41467-021-24734-0

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