Mobilizing dendritic cells for tolerance, priming, and chronic inflammation.
Mobilizing dendritic cells for tolerance, priming, and chronic inflammation.
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DOI：
10.1084/jem.189.4.611
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发表时间：
1999-02-15
期刊：
影响因子：
--
通讯作者：
Lanzavecchia A
中科院分区：
文献类型：
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作者：
Sallusto F;Lanzavecchia A
树突状细胞从血液向组织的迁移。树突状细胞（DC）功能的一个基本方面是它们的迁移能力。它允许它们对几乎所有身体组织中的传入抗原进行持续监视，并迅速报告给次级淋巴器官中的T细胞。在稳态条件下，DC从血液到组织和从组织到淋巴结的迁移速率可能非常低，并且这些DC中的大多数以休眠状态驻留在组织中，准备被病原体激活。然而，在炎症条件下，DC迁移的速率可以显著增加，以满足增加的抗原呈递需求。最近的几篇论文揭示了控制DC在诱导耐受、引发和慢性炎症中必须经历的各种步骤的机制。为了从血流中退出，DC像其他白细胞一样，首先需要与内皮细胞连接（图1）。这一过程对于随后的牢固粘附和外渗步骤至关重要，由选择素介导，选择素与特定细胞表面分子上的特定碳水化合物结合（1）。在这个问题上，Robert等证明了在外周血中循环的DC表达糖基化形式的P-选择素糖蛋白配体（PSGL）-1，其结合P-和E-选择素，其在内皮细胞上以低水平表达并被炎性刺激上调（2）。使用体内成像系统，他们表明DC束缚并滚动毛细血管内皮细胞表达的P-和E-选择素，并优先在炎症部位外渗。这一新的发现表明，血源性DC准备在炎症部位离开血液，从而允许这些APC在最需要它们的监视功能的地方快速募集。白细胞从血液到组织的募集在内皮细胞水平上受到调节，其中炎性细胞因子增加粘附分子和趋化因子的表达并诱导韦伯-帕拉德体的形成。这些代表P-选择素的储存颗粒（3，4），如最近两篇论文所示，也代表IL-8的储存颗粒（5，6）。用组胺或凝血酶刺激内皮细胞，可迅速动员韦伯-帕拉德小体的内容物。这种机制可以被视为一种形式的“记忆”，因为它允许已经暴露于炎症刺激的内皮细胞快速响应新的挑战，而不需要新的蛋白质合成，这具有明显的生理学和免疫病理学意义。
Migration of Dendritic Cells from Blood to Tissues. A fun-damental aspect of dendritic cell (DC) function is their capacity to migrate. It allows them to exert a continuous surveillance for incoming antigens in almost all body tissues and a prompt report to T cells in secondary lymphoid organs. Under steady state conditions, the rate of DC migration from blood to tissues and from tissues to lymph nodes is probably very low, and most of these DCs reside in the tissues in a dormant state ready to be activated by pathogens. However, in inflammatory conditions the rate of DC migration can be considerably increased to meet the increased requirement for antigen presentation. Several recent papers shed new light into the mechanisms that control the various steps that DCs have to undergo to perform their function in the induction of tolerance, priming, and chronic inflammation.To exit from the blood stream DCs, like other leukocytes, first need to tether to the endothelium (Fig. 1). This process, which is essential for the subsequent steps of firm adhesion and extravasation, is mediated by selectins that bind to specific carbohydrates on specialized cell surface molecules (1). In this issue, Robert et al. demonstrate that DCs that circulate in peripheral blood express a glycosylated form of P-selectin glycoprotein ligand (PSGL)-1 that binds to P-and E-selectins, which are expressed at low levels on endothelial cells and are upregulated by inflammatory stimuli (2). Using an in vivo imaging system, they show that DCs tether and roll on P-and E-selectins expressed by capillary endothelial cells and preferentially extravasate at sites of inflammation. This novel finding indicates that blood-borne DCs are poised to exit blood at inflammatory sites, thus allowing rapid recruitment of these APCs where their surveillance function is most needed. Recruitment of leukocytes from blood to tissues is regulated at the level of the endothelial cells, where inflammatory cytokines increase the expression of adhesion molecules and chemokines and induce the formation of Weibel-Palade bodies. These represent storage granules for P-selectin (3, 4) and, as shown in two recent papers, also for IL-8 (5, 6). The content of the Weibel-Palade bodies can be rapidly mobilized by stimulation of endothelial cells with histamin or thrombin. This mechanism can be viewed as a form of “memory,” since it allows endothelial cells that had been exposed to inflammatory stimuli to respond to a new challenge rapidly and without need for new protein synthesis, which has clear physiological as well as immunopathological significance.