Adaptive immune plasticity in MASH: Functional states, pathological consequences, and regulatory mechanisms

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease driven by both metabolic stress and immune dysregulation. A growing body of evidence suggests that adaptive immune cells exhibit significant functional plasticity during the progression and resolution of MASH. CD8+ T cells can assume various states, including pathogenic cytotoxicity, functional exhaustion, and tissue repair; CD4+ T cells exhibit enhanced Th1/Th17 programming, reduced Treg stability, and a functional shift toward Th17/Treg; and B cells undergo remodeling between regulatory, pro-inflammatory, and antibody-effect states. These functional states determine disease outcomes through distinct effector mechanisms. The cytotoxicity and inflammatory factors of pathogenic T cells promote hepatocyte damage, metabolic dysregulation, and hepatocyte stellate cell activation, while B-cell antigen presentation, cytokine, and antibody responses further amplify inflammation and fibrosis; conversely, Tregs, Bregs, and tissue-resident CD8+ T cells with reparative functions can limit inflammation or promote the resolution of fibrosis. Adaptive immune plasticity is, in turn, continuously shaped by the hepatic metabolic environment, in which glycolipid and mitochondrial metabolic reprogramming determine the metabolic basis of different functional states, while metabolite-driven epigenetic remodeling stabilizes corresponding transcriptional programs. Microbiome components and metabolic signals originating from the gut-liver axis further regulate the state of T and B cells within the liver. Consequently, the functional states of adaptive immune cells, their pathological effects, and their metabolic regulation collectively constitute a critical immunometabolic network linking metabolic dysregulation, chronic inflammation, and the progression of fibrosis, providing a unified mechanistic framework for understanding the sustained progression of MASH and tissue repair.