CCR2 and CCR6, but not endothelial selectins, mediate the accumulation of immature dendritic cells within the lungs of mice in response to particulate antigen
CCR2 and CCR6, but not endothelial selectins, mediate the accumulation of immature dendritic cells within the lungs of mice in response to particulate antigen
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DOI：
10.4049/jimmunol.175.2.874
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发表时间：
2005-07-15
影响因子：
4.4
通讯作者：
Curtis, JL
中科院分区：
文献类型：
--
作者：
Osterholzer, JJ;Ames, T;Curtis, JL
树突状细胞 (DC) 从炎症部位迁移到淋巴结以启动初级免疫反应，但在持续的肺部炎症过程中，DC 在肺部补充的分子机制尚不清楚。为了解决这个问题，我们分析了 Ag 引发小鼠对颗粒 T 细胞依赖性 Ag 羊红细胞 (SRBC) 气管内攻击的二次肺部免疫反应。我们研究了野生型 C57BL/6 小鼠和缺乏内皮选择素（CD62E 和 CD62P）或趋化因子受体 CCR2 或 CCR6 的同系基因靶向小鼠。 DC，定义为非自发荧光，MHC II类（+）CD11c（mod）细胞，使用流式细胞术和免疫组织学在血液、酶消化的碎肺和支气管肺泡灌洗液中检测到。与对照小鼠相比，Ag攻击增加了DC的频率和绝对数量，外周血中DC的频率和绝对数量在第1天达到峰值（频率增加6.5倍），肺碎屑中第3天（总DC增加20倍）和支气管肺泡灌洗液中第4天（总DC增加55倍）。大多数肺 DC 表达 CD11c、CD11b 和低水平的 MHC 11 类、CD40、CD80 和 CD86，与不成熟的骨髓表型一致。 DC 积累部分取决于 CCR2 和 CCR6，而不是内皮选择素。因此，在肺部炎症期间，来自血流的未成熟髓样 DC 取代了迁移的未成熟 DC，并暂时增加了肺内 APC 总数。早期 DC 的募集部分取决于 CCR2 穿过血管内皮，以及 CCR6 穿过肺泡上皮。循环未成熟 DC 的募集代表了调节免疫性肺部疾病的潜在治疗步骤。
Dendritic cells (DC) migrate from sites of inflammation to lymph nodes to initiate primary immune responses, but the molecular mechanisms by which DC are replenished in the lungs during ongoing pulmonary inflammation are unknown. To address this question, we analyzed the secondary pulmonary immune response of Ag-primed mice to intratracheal challenge with the particulate T cell-dependent Ag sheep erythrocytes (SRBC). We studied wild-type C57BL/6 mice and syngeneic gene-targeted mice lacking either both endothelial selectins (CD62E and CD62P), or the chemokine receptors CCR2 or CCR6. DC, defined as non-autofluorescent, MHC class II(+)CD11c(mod) cells, were detected in blood, enzyme-digested minced lung, and bronchoalveolar lavage fluid using flow cytometry and immunohistology. Compared with control mice, Ag challenge increased the frequency and absolute numbers of DC, peaking at day I in peripheral blood (6.5-fold increase in frequency), day 3 in lung mince (20-fold increase in total DC), and day 4 in bronchoalveolar lavage fluid (55-fold increase in total DC). Most lung DC expressed CD11c, CD11b, and low levels of MHC class 11, CD40, CD80, and CD86, consistent with an immature myeloid phenotype. DC accumulation depended in part upon CCR2 and CCR6, but not endothelial selectins. Thus, during lung inflammation, immature myeloid DC from the bloodstream replace emigrating immature DC and transiently increase total intrapulmonary APC numbers. Early DC recruitment depends in part on CCR2 to traverse vascular endothelium, plus CCR6 to traverse alveolar epithelium. The recruitment of circulating immature DC represents a potential therapeutic step at which to modulate immunological lung diseases.