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转运到淋巴结（LN）是由循环免疫细胞和高内皮小静脉（HEVs）之间的级联粘附相互作用介导的。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。在这里，我们解决了以下两个问题。(1)一种新型唾液黏液蛋白nepmucin在淋巴细胞归巢中的功能意义。我们发现了一种新的hev相关的唾液黏液蛋白，nepmucin（在Peyer’s patches中不表达的黏液蛋白）。与传统的黏液蛋白不同，nepmucin含有一个单一的v型Ig结构域和一个黏液蛋白样结构域。在LN hev中，内粘蛋白由l -选择蛋白反应性糖链修饰。我们发现用l -选择蛋白活性低聚糖修饰的粘蛋白样结构域支持淋巴细胞在生理流动条件下的滚动。此外，nepmucin通过其Ig结构域结合淋巴细胞，明显独立于淋巴细胞LFA-1和vla4，并与ICAM-1结合促进抗剪切淋巴细胞的结合。综上所述，这些结果表明，在LN hev中，nepmucin可能作为一种双重功能的粘附分子，通过不同的功能域介导淋巴细胞滚动和结合。(2)浆细胞样树突状细胞（pDCs）与hev的粘附相互作用。pDCs是天然的I型干扰素产生细胞，存在于LNs中，它们支持先天和适应性免疫反应。我们发现pDCs上的LFA-1/VLA-4及其配体在hev上的粘附和迁移过程中起关键作用。我们还发现，通过CCR7传递的信号在HEV细胞内pDCs向LNs的稳态运输中发挥重要作用。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混合动力汽车中pDCs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