ABSTRACT
Integrin α4ß7+ 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 α4ß7+ 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 α4ß7+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α4ß7 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 α4ß7+ CD4 and CD8 T cells, suggesting that α4ß7/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α4ß7+ T cells promote hepatic fibrosis progression. Analysis of hepatic α4ß7+ and α4ß7- CD4 T cells revealed that α4ß7+ CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that α4ß7+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α4ß7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.
Subject(s)
Cell Adhesion Molecules , Disease Progression , Integrins , Liver Cirrhosis , Liver , Mucoproteins , Animals , Liver Cirrhosis/pathology , Liver Cirrhosis/immunology , Liver Cirrhosis/metabolism , Cell Adhesion Molecules/metabolism , Mucoproteins/metabolism , Humans , Mice , Liver/pathology , Liver/metabolism , Integrins/metabolism , Male , Mice, Inbred C57BL , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Inflammation/pathology , CD8-Positive T-Lymphocytes/immunology , Immunoglobulins/metabolism , Disease Models, Animal , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Female , Antibodies, Monoclonal/pharmacologyABSTRACT
Integrin α 4 ß 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 ß 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 ß 7 + CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α 4 ß 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 ß 7 + CD4 and CD8 T cells suggesting that α 4 ß 7 /MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α 4 ß 7 + T cells promote hepatic fibrosis progression. Analysis of hepatic α 4 ß 7 + and α 4 ß 7 -CD4 T cells revealed that α 4 ß 7 + CD4 T cells enriched for markers of activation and proliferation demonstrating an effector phenotype. Notably, blockade of α 4 ß 7 or MAdCAM-1 did not affect the recruitment of Foxp3+ regulatory T cells, demonstrating the specificity of α 4 ß 7 /MAdCAM-1 axis in regulating effector T cell recruitment to the liver. The findings suggest that α 4 ß 7 + T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α 4 ß 7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.
