Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Non-alcoholic steatohepatitis (NASH) is characterized by chronic sterile inflammation that causes liver disease but the mechanisms of immune-mediated liver damage in NASH remain incomplete. An important feature of tissue-resident T cells in the liver is to integrate extracellular factors such as cytokines, nutrients and cell stress molecules into transcriptional networks to balance effector functions. Here, we identify murine and human CXCR6+CD8+ T cells as critical tissue-resident T cells causing liver damage in NASH after IL-15 and metabolic activation.

In NASH mice, we detected hepatic accumulation of CD8 T cells with phenotypes that combined tissue-residency (CXCR6) with effector (Granzymes) and exhaustion (PD-1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low FOXO1 transcription factor activity and were abundant in mouse and human NASH. Mechanistically, IL-15 induced FOXO1 down- and CXCR6 up-regulation, which rendered CXCR6+ CD8 T cells susceptible to metabolic stimuli in NASH livers, including acetate and extracellular adenosine triphosphate, and collectively triggered auto-aggression through TNF and FasL.Treatment of NASH mice with antibodies blocking the activity of TNF, FasL or IL-15 significantly ameliorated liver damage. Importantly, CXCR6+ CD8 T cells from mouse and human NASH livers had similar transcriptional signatures and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signaling through P2X7 purinergic receptors.

In summary, killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, thus mechanistically distinguishing auto-aggressive from protective T cell immunity.

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Artikel online veröffentlicht:
26. Januar 2022