Ato Manabu, Stäger Simona, Engwerda Christian R, Kaye Paul M
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Nat Immunol. 2002 Dec;3(12):1185-91. doi: 10.1038/ni861. Epub 2002 Nov 18.
Interaction between dendritic cells (DCs) and T cells is essential for the generation of cell-mediated immunity. Here we show that DCs from mice with chronic Leishmania donovani infection fail to migrate from the marginal zone to the periarteriolar region of the spleen. Stromal cells were fewer, which was associated with loss of CCL21 and CCL19 expression. The residual stromal cells and endothelium produced sufficient CCL21 to direct the migration of DCs transferred from naïve mice. However, DCs from infected mice had impaired migration both in naïve recipients and in vitro, in response to CCL21 and CCL19. Defective localization was attributable to tumor necrosis factor-alpha-dependent, interleukin 10-mediated inhibition of CCR7 expression. Effective immunotherapy was achieved with CCR7-expressing DCs, without the need to identify protective Leishmania antigens. Thus defective DC migration plays a major role in the pathogenesis of this disease and the immunosuppression is mediated, at least in part, through the spatial segregation of DCs and T cells.
树突状细胞（DCs）与T细胞之间的相互作用对于细胞介导的免疫反应的产生至关重要。在此我们表明，患有慢性杜氏利什曼原虫感染的小鼠的DCs无法从边缘区迁移至脾脏的动脉周围区域。基质细胞数量减少，这与CCL21和CCL19表达缺失有关。残留的基质细胞和内皮细胞产生足够的CCL21以引导从未感染小鼠转移来的DCs迁移。然而，来自感染小鼠的DCs在未感染受体体内以及体外对CCL21和CCL19的反应中迁移均受损。定位缺陷归因于肿瘤坏死因子-α依赖性、白细胞介素10介导的CCR7表达抑制。通过表达CCR7的DCs实现了有效的免疫治疗，而无需鉴定保护性利什曼原虫抗原。因此，DC迁移缺陷在该疾病的发病机制中起主要作用，并且免疫抑制至少部分是通过DCs和T细胞的空间隔离介导的。
