TY - JOUR
T1 - CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells
AU - Koda, Yuzo
AU - Teratani, Toshiaki
AU - Chu, Po Sung
AU - Hagihara, Yuya
AU - Mikami, Yohei
AU - Harada, Yosuke
AU - Tsujikawa, Hanako
AU - Miyamoto, Kentaro
AU - Suzuki, Takahiro
AU - Taniki, Nobuhito
AU - Sujino, Tomohisa
AU - Sakamoto, Michiie
AU - Kanai, Takanori
AU - Nakamoto, Nobuhiro
N1 - Funding Information:
This study was funded in part by Mitsubishi Tanabe Pharma Corporation. Y.K. is an employee of Mitsubishi Tanabe Pharma Corporation. The remaining authors declare no competing interests.
Funding Information:
We thank Y. Kitagawa, M. Shinoda, M. Kitagoh, Y. Abe, H. Yagi, and the medical staff of surgical department for collecting samples, H. Sato, S. Chiba, S. Fujimori, R. Aoki, A. Yamaguchi, S. Shiba, T. Katayama, Y. Takimoto, R. Morikawa, K. Yamataka, A. Ikura, R. Ishihara, and Y. Yoshimatsu (Keio University) for technical assistance. We thank Y. Imura, T. Amiya, and A. Matsumoto (Keio University) and S. Kato, K. Takara, A. Nishidate, and R. Sato (Mitsubishi Tanabe Pharma Corporation) for scientific discussion. We thank T. Miyamoto for bioinformatics support. We thank K. Sato (Miyazaki University) for providing Siglechdtr/dtr mice. This study was supported in part by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid (B) JP20H04129; Japan Agency for Medical Research and Development (AMED) 20gm1210001h0002 and 21fk0210096h0001; Takeda Science Foundation; the Mishima Kaiun Memorial Foundation; Yakult Bio-Science Foundation; and Keio University Medical Fund. We would like to thank Editage (www.editage.jp) for English language editing.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-24734-0
DO - 10.1038/s41467-021-24734-0
M3 - Article
C2 - 34294714
AN - SCOPUS:85111125732
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4474
ER -