Department of Molecular & Cellular Pathology, The University of Michigan, Ann Arbor, MI 48109, USA.
Eur J Immunol. 2010 Apr;40(4):1042-52. doi: 10.1002/eji.200939778.
Chemokines are important mediators of the immune response to pathogens, but can also promote chronic inflammatory states. Chemokine receptor 6 (CCR6) is found on immature DC and effector/memory T cells, and binds a single ligand, CCL20, with high affinity. Here, we investigated the role of CCL20 and CCR6 in a pulmonary viral infection caused by RSV, a ubiquitous virus that can cause severe pulmonary complications. Neutralization of CCL20 during RSV infection significantly reduced lung pathology and favored a Th1 effector response. CCR6-deficient animals recapitulated this phenotype, and additionally showed enhanced viral clearance when compared with WT mice. No differences were observed in migration of T cells to the lungs of CCR6(-/-) animals; however, a significant reduction was observed in numbers of conventional DC (cDC), but not plasmacytoid DC, in CCR6(-/-) mice. A pathogenic phenotype could be reconstituted in CCR6(-/-) mice by supplying cDC into the airway, indicating that mere number of cDC dictates the adverse response. Our data suggest that blockade of the CCL20/CCR6 pathway provides an environment whereby the attenuated recruitment of cDC alters the balance of innate immune cells and mediates the efficient antiviral response to RSV.
趋化因子是对病原体的免疫反应的重要介质，但也可以促进慢性炎症状态。趋化因子受体 6 (CCR6) 存在于未成熟的 DC 和效应/记忆 T 细胞上，并且以高亲和力结合单一配体 CCL20。在这里，我们研究了 CCL20 和 CCR6 在由 RSV 引起的肺部病毒感染中的作用，RSV 是一种普遍存在的病毒，可导致严重的肺部并发症。在 RSV 感染期间中和 CCL20 可显著减轻肺部病理并有利于 Th1 效应器反应。CCR6 缺陷型动物再现了这种表型，并且与 WT 小鼠相比，还显示出增强的病毒清除能力。在 CCR6(-/-)动物的 T 细胞向肺部的迁移中没有观察到差异;然而，在 CCR6(-/-)小鼠中观察到常规 DC(cDC)但不是浆细胞样 DC 的数量显著减少。通过向气道中提供 cDC 可以在 CCR6(-/-)小鼠中重建致病性表型，表明仅 cDC 的数量决定了不利的反应。我们的数据表明，阻断 CCL20/CCR6 途径提供了一种环境，其中 cDC 的减弱募集改变了固有免疫细胞的平衡，并介导了对 RSV 的有效抗病毒反应。
