Antigen-driven CD8⁺T cell clonal expansion is a prominent feature of MASH in humans and mice

Abstract

Background and Aims: Chronic liver disease (CLD) 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 in the liver in both cirrhosis and early stages of MASH to begin resolving their function in disease. Approach and Results: In these studies, we exhaustively interrogated liver resident T cell populations from individuals with cirrhosis and a murine model of MASH. Specifically, we defined the proteomic phenotype of liver resident T cells using flow cytometry and the transcriptional phenotype and T cell receptor repertoire of liver resident T cells using single cell sequencing. Conclusions: We discovered that 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, our data provide exhaustive documentation that during the progression of MASH, T cells undergo antigen-dependent T cell clonal expansion and implicate an active role for T cells in disease progression. These studies could lead to the identification of potential antigenic targets that drive T cell activation and recruitment to the liver in MASH.