Critical role for serum opsonins and complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in phagocytosis of Francisella tularensis by human dendritic cells (DC):: uptake of Francisella leads to activation of immature DC and intracellular survival of the bacteria
Critical role for serum opsonins and complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in phagocytosis of Francisella tularensis by human dendritic cells (DC):: uptake of Francisella leads to activation of immature DC and intracellular survival of the bacteria
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DOI：
10.1189/jlb.1205755
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发表时间：
2006-10-01
影响因子：
5.5
通讯作者：
Klimpel, Gary R.
中科院分区：
文献类型：
--
作者：
Ben Nasr, Abdelhakim;Haithcoat, Judith;Klimpel, Gary R.
土拉热弗朗西斯菌是已知的最具传染性的人类病原体之一。虽然已经了解了很多关于使用来自F.尽管在全北极土拉热菌亚种（B型）中，对人单核细胞衍生的未成熟树突状细胞（DC）的应答知之甚少。在这里，我们表明，最佳吞噬LVS的DC是依赖于血清调理。我们证明，补体因子C3衍生的调理素和DC表达的主要补体受体，整合素CR 3（CD 11b/CD 18）和CR 4（CD 11 c/CD 18），在这种粘附介导的吞噬作用中发挥关键作用。LVS诱导DC产生促炎细胞因子和上调共刺激表面蛋白（CD 40，CD 86和MHC II类），但抵抗杀伤。一旦被摄取，LVS在细胞内生长，导致DC死亡。DC成熟和细胞因子的产生诱导的直接接触/吞噬LVS或与细菌的可溶性产物的相互作用，并增强激活时，LVS用血清预处理。超声处理的LVS和来自LVS培养物的上清液是DC的有效激活剂，但LVS LPS未能激活DC成熟或细胞因子产生。血清处理的LVS迅速诱导（6小时内）的细胞因子，包括IL-10，一个有效的抑制巨噬细胞功能和下调Th 1样反应和Th 1反应诱导IL-12。这些结果表明，激活性（IL-12、IL-1 β和TNF-α）和抑制性（IL-10）细胞因子谱的同时产生可能有助于土拉菌病的免疫发病机制。J. Leukoc. 80：774-786; 2006.
Francisella tularensis is one of the most infectious human pathogens known. Although much has been learned about the immune response of mice using an attenuated live vaccine strain (LVS) derived from F. tularensis subspecies holarctica (Type B), little is known about the responses of human monocyte-derived immature dendritic cells (DC). Here, we show that optimal phagocytosis of LVS by DC is dependent on serum opsonization. We demonstrate that complement factor C3-derived opsonins and the major complement receptors expressed by DC, the integrins CR3 (CD11b/CD18) and CR4 (CD11c/ CD18), play a critical role in this adhesion-mediated phagocytosis. LVS induced proinflammatory cytokine production and up-regulation of costimulatory surface proteins (CD40, CD86, and MHC Class II) on DC but resisted killing. Once taken up, LVS grew intracellularly, resulting in DC death. DC maturation and cytokine production were induced by direct contact/ phagocytosis of LVS or interaction with soluble products of the bacteria, and enhanced activation was seen when LVS was pretreated with serum. Sonicated LVS and supernatants from LVS cultures were potent activators of DC, but LVS LPS failed to activate DC maturation or cytokine production. Serum-treated LVS rapidly induced (within 6 h) a number of cytokines including IL-10, a potent suppressor of macrophage functions and down-regulator of Th1-like responses and the Th1 response inducer IL-12. These results suggest that the simultaneous production of an activating (IL-12, IL-1 beta, and TNF-alpha) and a suppressing (IL-10) cytokine profile could contribute to the immunopathogenesis of tularemia. J. Leukoc. Biol. 80: 774-786; 2006.