Distinct Roles for CCR4 and CXCR3 in the Recruitment and Positioning of Regulatory T Cells in the Inflamed Human Liver
Distinct Roles for CCR4 and CXCR3 in the Recruitment and Positioning of Regulatory T Cells in the Inflamed Human Liver
复制标题
DOI：
10.4049/jimmunol.0901216
复制
发表时间：
2010-03-15
影响因子：
4.4
通讯作者：
Adams, David H.
中科院分区：
文献类型：
--
作者：
Oo, Ye H.;Weston, Chris J.;Adams, David H.
调节性T细胞（T-CTL）存在于慢性炎症部位，它们介导旁观者和Ag特异性抑制局部免疫应答。然而，很少有人知道的分子控制T-reg募集到发炎的人体组织。我们报告说，在人类肝脏疾病的炎症区域中，高达18%的T细胞是叉头家族转录调节盒P3（FoxP 3）（+）T-T细胞。我们从移植时切除的慢性炎症的人肝脏中分离出CD 4（+）CD 25（+）CD 127（低）FoxP 3（+）T-CRP;与血液来源的T-CRP相比，肝脏来源的T-CRP表达高水平的趋化因子受体CXCR 3和CCR 4。在使用人肝窦内皮细胞的基于流动的粘附试验中，T-TRB使用CXCR 3和α 4 β 1结合和迁移，而CCR 4不起作用。CCR 4配体CCL 17和CCL 22在健康肝脏中不存在，但在慢性炎症肝脏中检测到它们，其中它们的表达限于炎性浸润物内的树突状细胞（DC）。这些DC与实质和间隔区的CD 8 T细胞和CCR 4（+）T-T细胞密切相关。离体，肝源性T-CRP迁移到肝内DC分泌的CCR 4配体。我们认为CXCR 3通过肝窦内皮介导T-CRP的募集，而DCs分泌的CCR 4配体将T-CRP募集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的肝炎部位的T细胞的募集和定位中发挥不同的作用。免疫学杂志，2010，184：2886-2898。
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.