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

doi:10.1038/s41467-021-24734-0

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

Nat Commun. 2021 Jul 22;12(1):4474. doi: 10.1038/s41467-021-24734-0.

Authors

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
² Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan.
³ Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
⁴ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. takagast@z2.keio.jp.
⁵ Japan Agency for Medical Research and Development, AMED, Tokyo, Japan. takagast@z2.keio.jp.
⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. nobuhiro@z2.keio.jp.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adoptive Transfer
Adult
Aged
Aged, 80 and over
Animals
Apoptosis / immunology
CD8-Positive T-Lymphocytes / immunology*
Disease Models, Animal
Disease Progression
Female
Hepatic Stellate Cells / immunology
Hepatic Stellate Cells / pathology*
Humans
Immunologic Memory
Interleukin-15 / immunology
Liver Cirrhosis / immunology*
Liver Cirrhosis / pathology*
Liver Cirrhosis / therapy
Male
Mice
Mice, Inbred C57BL
Middle Aged
Non-alcoholic Fatty Liver Disease / immunology*
Non-alcoholic Fatty Liver Disease / pathology*
Non-alcoholic Fatty Liver Disease / therapy
Receptors, CCR5 / immunology
Young Adult

Substances

CCR5 protein, mouse
Interleukin-15
Receptors, CCR5