Distinct Roles for CCR4 and CXCR3 in the Recruitment and Positioning of Regulatory T Cells in the Inflamed Human Liver

Abstract

Regulatory T cells (T_regs) are found at sites of chronic inflammation where they mediate bystander and Ag-specific suppression of local immune responses. However, little is known about the molecular control of T_reg recruitment into inflamed human tissues. We report that up to 18% of T cells in areas of inflammation in human liver disease are forkhead family transcriptional regulator box P3 (FoxP3)⁺ T_regs. We isolated CD4⁺CD25⁺CD127^lowFoxP3⁺ T_regs from chronically inflamed human liver removed at transplantation; compared with blood-derived T_regs, liver-derived T_regs express high levels of the chemokine receptors CXCR3 and CCR4. In flow-based adhesion assays using human hepatic sinusoidal endothelium, T_regs used CXCR3 and α4β1 to bind and transmigrate, whereas CCR4 played no role. The CCR4 ligands CCL17 and CCL22 were absent from healthy liver, but they were detected in chronically inflamed liver where their expression was restricted to dendritic cells (DCs) within inflammatory infiltrates. These DCs were closely associated with CD8 T cells and CCR4⁺ T_regs in the parenchyma and septal areas. Ex vivo, liver-derived T_regs migrated to CCR4 ligands secreted by intrahepatic DCs. We propose that CXCR3 mediates the recruitment of T_regs via hepatic sinusoidal endothelium and that CCR4 ligands secreted by DCs recruit T_regs to sites of inflammation in patients with chronic hepatitis. Thus, different chemokine receptors play distinct roles in the recruitment and positioning of T_regs at sites of hepatitis in chronic liver disease.