Metabolic Dysfunction-Associated Steatohepatitis (MASH) results in clonal expansion of CD8+ T cells with diverse antigen reactivities 2637

Abstract Description Chronic liver disease due to MASH is predicted to become the primary cause of liver transplantation. Yet, the contribution of T cells in MASH remains unresolved. Previously, we published that CD8+ T cell clonal expansion is a common event in the liver of both murine MASH and MASH-induced cirrhosis in humans. Here, we characterized the timing of clonal expansion and breadth antigen reactivity of the T cell receptors (TCRs) in MASH. To achieve this, we performed single cell TCR sequencing of the liver resident T cells throughout the course of disease and interrogated the antigen reactivity of clonally expanded TCRs from the liver of mice with MASH using unbiased peptide libraries. We found that CD8+ T cell clonal expansion occurs prior to the onset of fibrosis and that the clonally expanded T cells from the liver of mice with MASH did not share a common specificity profile. Moreover, immunization of mice with a mixture of stimulatory peptides resulted in amplification of liver pathology in murine MASH. These studies implicate a pathogenic role for CD8+ T cell clonal expansion in the progression of MASH. However, our studies demonstrate that there is a diverse repertoire of antigens that drive clonal expansion in the liver during MASH. Thus, current studies are aimed at identifying biologic origins of the antigenic drivers of T cell activation in MASH and determining if modulation of T cell activation and function can change the progression of this pervasive disease. Topic Categories Immune Mechanisms of Human Disease (HUM)