Integrin α₄β₇+ T cells perpetuate tissue injury in chronic inflammatory diseases, yet their role in hepatic fibrosis progression remains poorly understood. Here, we report increased accumulation of α₄β₇+ T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl₄-induced liver fibrosis was associated with enrichment of intrahepatic α₄β₇+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α₄β₇ or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl₄-treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of α₄β₇+ CD4 and CD8 T cells, suggesting that α₄β₇/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α₄β₇+ T cells promote hepatic fibrosis progression. Analysis of hepatic α₄β₇+ and α₄β₇- CD4 T cells revealed that α₄β₇+ CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that α₄β₇+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α₄β₇ or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.

The immunosuppressive T regulatory cells (Tregs) regulate immune responses and maintain immune homeostasis, yet their functions in metabolic dysfunction-associated steatotic liver disease (MASLD) remain controversial. Here we report increased accumulation of Tregs and effector T cells within the liver parenchyma of mice fed a Western diet (WD). This pattern was also observed in MASH patients, where an increase in intrahepatic Tregs was noted. In the absence of adaptive immune cells in Rag1 KO mice, WD promoted accumulation of intrahepatic neutrophils and macrophages and exacerbated hepatic inflammation and fibrosis. Similarly, targeted Treg depletion exacerbated WD-induced hepatic inflammation and fibrosis. In Treg-depleted mice, hepatic injury was associated with increased accumulation of neutrophils, macrophages, and activated T cells in the liver. Conversely, induction of Treg numbers using recombinant IL2/αIL2 mAb cocktail reduced hepatic steatosis, inflammation, and fibrosis in WD-fed mice. Analysis of intrahepatic Tregs from WD-fed mice revealed a phenotypic signature of impaired Treg function in MASLD. Ex vivo functional studies showed that glucose and palmitate, but not fructose, impaired the immunosuppressive ability of Treg cells. The findings indicate that the liver microenvironment in MASLD impairs the ability of Tregs to suppress effector immune cell activation, thus perpetuating chronic inflammation and driving MASLD progression.

Next-generation sequencing can identify previously uncharacterized gene expression patterns in disease. Beyond differentially expressed gene (DEG) analysis, we investigated the ability of within-population diversity (α-diversity) of the transcriptome to reveal additional biological information in alcohol-associated liver disease (ALD), comparing differential Shannon diversity (DSD) to transcriptome heterogeneity changes. RNA sequencing data from normal livers and patients with early ALD and severe AH were analyzed. α-Diversity indices and percentage Shannon diversity of a gene, which refers to this gene’s contribution to total Shannon entropy, were calculated. Ingenuity pathway analysis identified canonical pathways determined by DEG and DSD approaches. ALD significantly decreased hepatic transcriptome α-diversity, correlating with increased relative contribution of select genes. These changes were driven by lower-abundance gene expression loss. DEG and DSD analyses showed overlapping genes and canonical pathways, but DSD also identified additional genes and pathways not highlighted by DEGs, including fatty acid oxidation, extracellular matrix degradation, and cholesterol metabolism pathways that may represent additional therapeutic targets. Importantly, DSD more effectively identified differences between ASH and AH. Overall, α-diversity analysis revealed that ALD progressively reduces transcriptome heterogeneity, and that DSD provides complementary insights into disease mechanisms missed by standard approaches.