Glycobiology Unit, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Immunity. 2010 Nov 24;33(5):817-29. doi: 10.1016/j.immuni.2010.10.018.
Heparan sulfate can bind several adhesion molecules involved in lymphocyte trafficking. However, the in vivo function of endothelial heparan sulfate in lymphocyte homing and stimulation of the immune response has not been elucidated. Here, we generated mutant mice deficient in the enzyme Ext1, which is required for heparan sulfate synthesis, in a Tek-dependent and inducible manner. Chemokine presentation was diminished in the mutant mice, causing the lack of appropriate integrin-mediated adhesion, and resulted in a marked decrease in lymphocyte sticking to high endothelial venules and in recruitment of resident dendritic cells through lymphatic vessels to the lymph nodes. As a consequence, mutant mice displayed a severe impairment in lymphocyte homing and a compromised contact hypersensitivity response. By contrast, lymphocyte rolling was increased because of loss of electrostatic repulsion by heparan sulfate. These results demonstrate critical roles of endothelial heparan sulfate in immune surveillance and immune response generation.
硫酸乙酰肝素可以结合几种参与淋巴细胞迁移的黏附分子。然而，内皮细胞硫酸乙酰肝素在淋巴细胞归巢和刺激免疫反应中的体内功能尚未阐明。在这里，我们生成了突变小鼠，这些小鼠以 Tek 依赖性和诱导性的方式缺乏合成硫酸乙酰肝素所必需的酶 Ext1。突变小鼠中的趋化因子呈递减少，导致适当的整合素介导的黏附缺失，并导致淋巴细胞与高内皮小静脉的黏附以及通过淋巴管向淋巴结募集常驻树突状细胞明显减少。因此，突变小鼠表现出严重的淋巴细胞归巢缺陷和接触超敏反应受损。相比之下，由于硫酸乙酰肝素的静电排斥丧失，淋巴细胞滚动增加。这些结果表明内皮细胞硫酸乙酰肝素在免疫监视和免疫反应产生中起着关键作用。
