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

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<jats:title>Abstract</jats:title><jats:p>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<jats:sup>+</jats:sup> tissue-resident memory CD8<jats:sup>+</jats:sup> T (CD8<jats:sup>+</jats:sup> Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69<jats:sup>+</jats:sup>CD103<jats:sup><jats:bold>−</jats:bold></jats:sup>CD8<jats:sup>+</jats:sup> Trm cell enrichment in NASH resolution livers. The reduction of liver CD8<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup>CD8<jats:sup>+</jats:sup> Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8<jats:sup>+</jats:sup> Trm in fibrosis resolution.</jats:p>

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  • Nature Communications

    Nature Communications 12 (1), 4474-, 2021-07-22

    Springer Science and Business Media LLC

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