Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver

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(low)FoxP3(+) 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 alpha 4 beta 1 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. The Journal of Immunology, 2010, 184: 2886-2898.