Abstract
BACKGROUND AND AIMS: Chronic liver disease due to metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated hepatic immune responses. T lymphocytes have been shown to accumulate in the liver during MASH, but the cause and consequence of T cell accumulation in the liver remain unclear. Our study aimed to define the phenotype and T cell receptor diversity of T cells from human cirrhotic livers and an animal model of MASH to begin resolving their function in disease. APPROACH AND RESULTS: In these studies, we evaluated differences in T cell phenotype in the context of liver disease we isolated liver resident T cell populations from individuals with cirrhosis and a murine model of MASH. Using both 5' single cell sequencing and flow cytometry we defined the phenotype and T cell receptor repertoire of liver resident T cells during health and disease. CONCLUSIONS: MASH-induced cirrhosis and diet-induced MASH in mice resulted in the accumulation of activated and clonally expanded T cells in the liver. The clonally expanded T cells in the liver expressed markers of chronic antigenic stimulation, including PD1 , TIGIT and TOX . Overall, this study establishes for the first time that T cells undergo antigen-dependent clonal expansion and functional differentiation during the progression of MASH. These studies could lead to the identification of potential antigenic targets that drive T cell activation, clonal expansion, and recruitment to the liver during MASH.