Selective targeting of α 4 β 7 /MAdCAM-1 axis suppresses liver fibrosis by reducing proinflammatory T cell recruitment to the liver

Abstract

Integrin α ₄ β ₇ + 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 α ₄ β ₇ + T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl ₄ -induced liver fibrosis was associated with enrichment of intrahepatic α ₄ β ₇ + CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α ₄ β ₇ or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl ₄ treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of α ₄ β ₇ + CD4 and CD8 T cells suggesting that α ₄ β ₇ /MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α ₄ β ₇ + T cells promote hepatic fibrosis progression. Analysis of hepatic α ₄ β ₇ + and α ₄ β ₇ -CD4 T cells revealed that α ₄ β ₇ + CD4 T cells enriched for markers of activation and proliferation demonstrating an effector phenotype. Notably, blockade of α ₄ β ₇ or MAdCAM-1 did not affect the recruitment of Foxp3+ regulatory T cells, demonstrating the specificity of α ₄ β ₇ /MAdCAM-1 axis in regulating effector T cell recruitment to the liver. The findings suggest that α ₄ β ₇ + T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α ₄ β ₇ or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.