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Metabolic activation of T cells – driver of liver disease in NASH

8th Munich Metabolomics Symposium Applications of clinical metabolomics in oncology and cardiovascular diseases Virtual event November 12th, 2021 Part 1 - Oncology & Immunology Organized by Helmholtz Zentrum Munich, Technical University Munich, and biocrates Prof. Dr. Percy Knolle Technical University Munich, Germany Abstract: The liver is an organ with unique immunological functions that is known for its ability to induce immune tolerance. Notwithstanding this tolerogenic role, the liver is target of immune-mediated damage in chronic viral hepatitis, in autoimmune hepatitis and in non-alcoholic steatohepatitis (NASH). While virus-specific T cell immunity and autoimmune T cells are known to drive chronic liver damage, the cell population mediating liver damage in non-alcoholic steatohepatitis has remained elusive. Various metabolic malfunctions may contribute to increased innate immunity and hepatocyte death in NASH. We have recently discovered a key function of T cells that mediates liver damage in NASH. We detected a unique population of tissue-resident CXCR6+ CD8 T cells in NASH livers that had downregulated the transcription factor Foxo1. Following exposure to acetate that is present at increased concentrations in NASH livers, CXCR6+Foxo1low CD8 T cells became auto-aggressive and killed hepatocytes. Such killing of hepatocytes was independent from MHC-I expression on hepatocytes and did not require antigen-presentation or T cell receptor signaling. Instead, CXCR6+Foxo1low CD8 T cells responded to metabolic cues from the environment such as extracellular ATP. Activation of auto-aggressive CD8 T cells and triggering of cell death execution was mediated through purinergic receptors such as P2X7. Our data demonstrate a metabolic activation of T cells that triggers auto-aggressive tissue damage and is mechanistically distinct from T cell receptor mediated T cell activation, which opens new avenues for targeted immune intervention in NASH and its consequences such as liver cancer.