Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products.
Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products.
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DOI：
10.1084/jem.182.2.389
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发表时间：
1995-08-01
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;Cella M;Danieli C;Lanzavecchia A
我们先前已经证明，人外周血低密度单核细胞在粒细胞/巨噬细胞集落刺激因子（GM-CSF）和白细胞介素（IL）-4中培养可发育成树突状细胞（DC），其在向T细胞呈递可溶性抗原方面非常有效。为了确定负责有效的抗原捕获的机制，我们使用异硫氰酸荧光素-葡聚糖、辣根过氧化物酶和荧光黄研究了DC的内吞能力。我们发现DC使用两种不同的抗原捕获机制。第一种是通过巨胞饮作用的高水平的液相摄取。与其他细胞类型相比，DC中的巨胞饮作用是组成性的，允许大量液体的连续内化。第二种捕获机制是通过甘露糖受体（MR）介导的，其在DC上以高水平表达。在低配体浓度下，MR可以在连续轮次中将大量配体递送至细胞。因此，虽然巨胞饮作用赋予DC捕获任何可溶性抗原的高能力、不饱和机制，但MR提供了额外的抗原捕获能力，并对非自身分子具有一定程度的选择性。除了它们的高内吞能力之外，来自GM-CSF + IL-4依赖性培养物的DC的特征在于存在含有高水平的II类分子、组织蛋白酶D和溶酶体相关膜蛋白-1的大的细胞内区室，并且可快速接近内吞标记物。我们研究了DC捕获和处理抗原的能力是否可以通过外源性刺激来调节。我们发现，DCs对肿瘤坏死因子α、CD 40配体、IL-1和脂多糖的反应具有一系列协调的变化，包括巨胞饮和Fc受体的下调、II类区室的消失以及粘附和共刺激分子的上调。这些变化发生在1-2 d内，并且是不可逆的，因为当成熟诱导刺激被去除时，胞饮作用和II类隔室都不能恢复。MR的特异性和对炎性刺激的反应能力使DC向T细胞呈递感染性非自身抗原的能力最大化。
We have previously demonstrated that human peripheral blood low density mononuclear cells cultured in granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 develop into dendritic cells (DCs) that are extremely efficient in presenting soluble antigens to T cells. To identify the mechanisms responsible for efficient antigen capture, we studied the endocytic capacity of DCs using fluorescein isothiocyanate-dextran, horseradish peroxidase, and lucifer yellow. We found that DCs use two distinct mechanisms for antigen capture. The first is a high level of fluid phase uptake via macropinocytosis. In contrast to what has been found with other cell types, macropinocytosis in DCs is constitutive and allows continuous internalization of large volumes of fluid. The second mechanism of capture is mediated via the mannose receptor (MR), which is expressed at high levels on DCs. At low ligand concentrations, the MR can deliver a large number of ligands to the cell in successive rounds. Thus, while macropinocytosis endows DCs with a high capacity, nonsaturable mechanism for capture of any soluble antigen, the MR gives an extra capacity for antigen capture with some degree of selectivity for non-self molecules. In addition to their high endocytic capacity, DCs from GM-CSF + IL-4-dependent cultures are characterized by the presence of a large intracellular compartment that contains high levels of class II molecules, cathepsin D, and lysosomal- associated membrane protein-1, and is rapidly accessible to endocytic markers. We investigated whether the capacity of DCs to capture and process antigen could be modulated by exogenous stimuli. We found that DCs respond to tumor necrosis factor alpha, CD40 ligand, IL-1, and lipopolysaccharide with a coordinate series of changes that include downregulation of macropinocytosis and Fc receptors, disappearance of the class II compartment, and upregulation of adhesion and costimulatory molecules. These changes occur within 1-2 d and are irreversible, since neither pinocytosis nor the class II compartment are recovered when the maturation-inducing stimulus is removed. The specificity of the MR and the capacity to respond to inflammatory stimuli maximize the capacity of DCs to present infectious non-self antigens to T cells.