Adhesive interactions governing immune-cell trafficking across HEVs and its regulation by infectious stimulation

淋巴细胞和某些抗原提呈细胞从血液运输到淋巴结(LN)是由循环免疫细胞和高内皮微静脉(HEV)之间的一系列黏附相互作用调节的。黏附相互作用包括免疫细胞在HEV上的滚动、牢固黏附和跨内皮细胞迁移。控制粘附性相互作用的分子机制仍有待于充分阐明。在这里，我们解决了以下两个问题。(1)一种新的唾液粘蛋白内粘蛋白在淋巴细胞归巢至LNS中的功能意义。我们发现了一种新的HEV相关唾液粘蛋白，nepmucin(Peyer‘s斑块中不表达的粘蛋白)。与传统唾液粘蛋白不同的是，内粘蛋白含有一个V型Ig结构域和一个粘蛋白样结构域。在LN HEV中，内粘蛋白由L-选择素-反应糖链修饰。我们发现，粘蛋白样区L-选择素反应性寡糖修饰的内粘蛋白在生理流动条件下支持淋巴细胞滚动。…此外，内粘蛋白通过其Ig结构域与淋巴细胞结合，明显独立于淋巴细胞LFA-1和VLA-4，并与ICAM-1结合促进抗剪切淋巴细胞结合。综上所述，这些结果提示nep黏蛋白可能在LN HEV中作为一种双重功能的黏附分子，通过不同的功能结构域介导淋巴细胞滚动和结合。(2)浆细胞样树突状细胞(PDC)与HEV之间的黏附作用。PDC是天然的I型干扰素产生细胞，存在于LNS中，既支持先天免疫反应，也支持获得性免疫反应。我们发现PDCs上的LFA-1/VLA-4及其在HEV上的配体在PDCs的黏附和迁移过程中起着关键作用。我们还发现，通过CCR7的信号在pDC通过HEV细胞向LNS的动态平衡运输中发挥着重要作用。这些观察结果共同表明，某些细胞黏附分子和趋化因子信号协同调节pDC在HEV之间的运输。较少

Trafficking of lymphocytes and certain antigen presenting cells from the blood into lymph nodes (LN) is mediated by a cascade of adhesive interactions between circulating immune-cells and high endothelial venules (HEVs). The adhesive interactions include rolling, firm adhesion and transendothelial migration of immune-cells across the HEVs. Molecular mechanisms governing the adhesive interactions still remain to be fully elucidated. Here we addressed two following issues. (1)Functional significance of a novel sialomucin nepmucin in lymphocyte homing to LNs. We identified a novel HEV-associated sialomucin, nepmucin (mucin not expressed in Peyer's patches). Unlike conventional sialomucins, nepmucin contains a single V-type Ig domain and a mucin-like domain. In LN HEVs, nepmucin is decorated by L-selectin-reactive sugar chains. We found that nepmucin modified with L-selectin-reactive oligosaccharides in its mucin-like domain supported lymphocyte rolling under physiological flow conditions. … More Furthermore, nepmucin bound lymphocytes via its Ig domain, apparently independent of lymphocyte LFA-1 and VLA-4,and promoted shear-resistant lymphocyte binding in combination with ICAM-1. Taken together, these results suggest that nepmucin may serve as a dual-functioning adhesion molecule in LN HEVs, mediating both lymphocyte rolling and binding via different functional domains. (2)Adhesive interactions between plasmacytoid dendritic cells (pDCs) and HEVs. pDCs are natural type I interferon-producing cells, and are found in LNs, where they support both innate and adaptive immune responses. We found that LFA-1/VLA-4 on pDCs and their ligands on HEVs play critical roles in the adhesion and transmigration process of pDCs. We also found that signals through CCR7 play an important role in homeostatic trafficking of pDCs into LNs across HEV cells. These observations collectively suggest that certain cell adhesion molecules and chemokine signals cooperatively regulate trafficking of pDCs across HEVs. Less