Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice
Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice
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DOI：
10.1172/jci36731
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发表时间：
2009-07-01
影响因子：
15.9
通讯作者：
Weiser, Jeffrey N.
中科院分区：
文献类型：
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作者：
Zhang, Zhe;Clarke, Thomas B.;Weiser, Jeffrey N.
粘膜表面的微生物定植可能是疾病进展的初始事件，并且通常是一个短暂的过程。对于在小鼠模型中研究的细胞外病原体肺炎链球菌，鼻咽携带会在数周内消除，并且需要细胞免疫而不是体液免疫。在这里，我们证明原发感染导致 TLR2 依赖性单核细胞/巨噬细胞募集到上气道腔中，在那里它们吞噬肺炎球菌。通过鼻内滴注脂质体氯膦酸盐来消除管腔单核细胞/巨噬细胞，从而减少肺炎球菌的清除。有效清除定植需要 TLR2 信号转导来产生肺炎球菌特异性表达 IL-17 的 CD4(+)T 细胞群。 IL-17A 或 CD4(+)T 细胞的耗竭足以阻止单核细胞/巨噬细胞的募集，从而实现有效的晚期肺炎球菌清除。与幼稚小鼠相比，先前定植的小鼠表现出增强的早期清除能力，这与管腔中性粒细胞更强劲的流入相关。至于初级定植，这些细胞反应需要 Th17 免疫。我们的研究结果表明，募集到粘膜表面的单核细胞/巨噬细胞和中性粒细胞分别是清除原发性和继发性细菌定植的关键效应器。
Microbial colonization of mucosal surfaces may be an initial event in the progression to disease, and it is often a transient process. For the extracellular pathogen Streptococcus pneumoniae studied in a mouse model, nasopharyngeal carriage is eliminated over a period of weeks and requires cellular rather than humoral immunity. Here, we demonstrate that primary infection led to TLR2-dependent recruitment of monocyte/macrophages into the upper airway lumen, where they engulfed pneumococci. Pharmacologic depletion of luminal monocyte/macrophages by intranasal instillation of liposomal clodronate diminished pneumococcal clearance. Efficient clearance of colonization required TLR2 signaling to generate a population of pneumococcal-specific IL-17-expressing CD4(+)T cells. Depletion of either IL-17A or CD4(+)T cells was sufficient to block the recruitment of monocyte/macrophages that allowed for effective late pneumococcal clearance. In contrast with naive mice, previously colonized mice showed enhanced early clearance that correlated with a more robust influx of luminal neutrophils. As for primary colonization, these cellular responses required Th17 immunity. Our findings demonstrate that monocyte/macrophages and neutrophils recruited to the mucosal surface are key effectors in clearing primary and secondary bacterial colonization, respectively.