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

Author

Listed:
  • Yuzo Koda

    (Keio University School of Medicine
    Mitsubishi Tanabe Pharma Corporation)

  • 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
    Japan Agency for Medical Research and Development, AMED)

  • Nobuhiro Nakamoto

    (Keio University School of Medicine)

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.

Suggested Citation

  • Yuzo Koda & Toshiaki Teratani & Po-Sung Chu & Yuya Hagihara & Yohei Mikami & Yosuke Harada & Hanako Tsujikawa & Kentaro Miyamoto & Takahiro Suzuki & Nobuhito Taniki & Tomohisa Sujino & Michiie Sakamot, 2021. "CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24734-0
    DOI: 10.1038/s41467-021-24734-0
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    Cited by:

    1. Juliane Glaubitz & Anika Wilden & Janine Golchert & Georg Homuth & Uwe Völker & Barbara M. Bröker & Thomas Thiele & Markus M. Lerch & Julia Mayerle & Ali A. Aghdassi & Frank U. Weiss & Matthias Sendle, 2022. "In mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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