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

淋巴细胞和某些抗原呈递细胞从血液运输到淋巴结（LN）中是由循环免疫细胞和高内皮微静脉（HEV）之间的粘附相互作用级联介导的。粘附相互作用包括免疫细胞在HEV上的滚动、牢固粘附和跨内皮迁移。控制粘附相互作用的分子机制仍有待充分阐明。在此，我们讨论了以下两个问题。（1）新型唾液粘蛋白nepmucin在淋巴细胞归巢至淋巴结中的功能意义。我们鉴定了一种新的HEV相关的唾液粘蛋白，nepmucin（Peyer氏斑中不表达的粘蛋白）。与传统的唾液粘蛋白不同，nepmucin含有单个V型IG结构域和粘蛋白样结构域。在LN HEV中，髓粘蛋白被L-选择素反应性糖链修饰。我们发现，在其粘蛋白样结构域中用L-选择素反应性寡糖修饰的nepmucin在生理流动条件下支持淋巴细胞滚动。 ...更多信息 此外，nepmucin结合淋巴细胞通过其IG域，显然独立于淋巴细胞LFA-1和VLA-4，并促进抗剪切淋巴细胞结合ICAM-1。两者合计，这些结果表明，nepmucin可能作为一个双功能的粘附分子在LN HEV，介导淋巴细胞滚动和绑定通过不同的功能域。（2）浆细胞样树突状细胞（pDC）与HEV之间的粘附相互作用。pDC是天然的I型干扰素产生细胞，并且存在于LN中，在LN中它们支持先天性和适应性免疫应答。我们发现pDC上的LFA-1/VLA-4及其在HEV上的配体在pDC的粘附和迁移过程中起着关键作用。我们还发现，通过CCR 7的信号在pDC跨HEV细胞进入LN的稳态运输中起重要作用。这些观察结果共同表明，某些细胞粘附分子和趋化因子信号协同调节pDC跨HEV的运输。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