Centre for Liver Research, Institute of Biomedical Research, The University of Birmingham Medical School, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.
J Immunol. 2010 Mar 15;184(6):2886-98. doi: 10.4049/jimmunol.0901216. Epub 2010 Feb 17.
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 alpha4beta1 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.
调节性 T 细胞（Tregs）存在于慢性炎症部位，通过旁分泌和抗原特异性抑制局部免疫反应来发挥作用。然而，人们对 Tregs 募集到炎症人类组织中的分子调控知之甚少。我们报告称，在人类肝脏疾病炎症区域中，高达 18%的 T 细胞是叉头框 P3（FoxP3）阳性 Tregs。我们从移植时切除的慢性炎症人类肝脏中分离出 CD4+CD25+CD127(low)FoxP3+Tregs；与血液来源的 Tregs 相比，肝脏来源的 Tregs 表达高水平的趋化因子受体 CXCR3 和 CCR4。在使用人肝窦内皮细胞的基于流式的粘附测定中，Tregs 使用 CXCR3 和 α4β1 来结合和迁移，而 CCR4 不起作用。CCR4 配体 CCL17 和 CCL22 不存在于健康肝脏中，但在慢性炎症肝脏中检测到，其表达仅限于炎症浸润中的树突状细胞 (DC)。这些 DC 与实质和间隔区域中的 CD8 T 细胞和 CCR4+Tregs 密切相关。在体外，肝脏来源的 Tregs 迁移到肝内 DC 分泌的 CCR4 配体。我们提出，CXCR3 通过肝窦内皮细胞介导 Tregs 的募集，而 DC 分泌的 CCR4 配体募集 Tregs 到慢性肝炎患者的炎症部位。因此，不同的趋化因子受体在慢性肝病中肝炎部位 Tregs 的募集和定位中发挥不同的作用。
