Molecular pathways defining human CD8 T cell auto-aggression in immune-mediated liver diseases

Introduction Immunopathology in immune-mediated liver diseases such as autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) or metabolic-dysfunction associated steatohepatitis (MASH) is considered to be caused by cytotoxic CD8 T cells but the molecular mechanisms remain incompletely understood. Here, we report the identification of auto-aggressive CD8 T cells (aaCD8 T cells) in liver tissues of these patients that developed in response to IL-15-stimulation and efficiently killed hepatocytes in the absence of MHC-restricted antigen recognition.

Methods: Single-cell RNA-seq of CD8 T cells (ex vivo/in vitro), flow cytometry and cytotoxicity assays were performed to study phenotype and function of human aaCD8 T cells.

Results: scRNA-seq of IL-15 activated human CD8 T cells in vitro identified CD8 T cells with an auto-aggression signature that was characterized by high levels of HLA type II molecules and granzymes. Using bioinformatic approaches, we found CD8 T cells with an auto-aggression gene signature to be enriched in tissues of patients with AIH and PSC. Mechanistically, aaCD8 T cells that were activated by extracellular histones eliminated target cells dependent on the release of granzymes and the surface expression of c-type lectin receptors Clec2B and D. Blockade of SYK signaling downstream of Clec2B/D completely prevented CD8 T cell auto-aggression whereas killing of target cells by NK cells or antigen-specific CD8 T cells was unaffected.

Conclusion: We defined molecular pathways of MHC-unrestricted CD8 T-cell auto-aggression in tissues of patients with immune-mediated liver diseases that could open new avenues for the treatment of immune-mediated diseases in the liver and in other organs.

Publication History

Article published online:
20 January 2025