Thiemann Sandra, Man Jeanette H, Chang Margaret H, Lee Benhur, Baum Linda G
From the Departments of Pathology and Laboratory Medicine and.
Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 and.
J Biol Chem. 2015 Sep 11;290(37):22662-77. doi: 10.1074/jbc.M115.644799. Epub 2015 Jul 27.
During inflammation, dendritic cells emigrate from inflamed tissue across the lymphatic endothelium into the lymphatic vasculature and travel to regional lymph nodes to initiate immune responses. However, the processes that regulate dendritic cell tissue egress and migration across the lymphatic endothelium are not well defined. The mammalian lectin galectin-1 is highly expressed by vascular endothelial cells in inflamed tissue and has been shown to regulate immune cell tissue entry into inflamed tissue. Here, we show that galectin-1 is also highly expressed by human lymphatic endothelial cells, and deposition of galectin-1 in extracellular matrix selectively regulates migration of specific human dendritic cell subsets. The presence of galectin-1 inhibits migration of immunogenic dendritic cells through the extracellular matrix and across lymphatic endothelial cells, but it has no effect on migration of tolerogenic dendritic cells. The major galectin-1 counter-receptor on both dendritic cell populations is the cell surface mucin CD43; differential core 2 O-glycosylation of CD43 between immunogenic dendritic cells and tolerogenic dendritic cells appears to contribute to the differential effect of galectin-1 on migration. Binding of galectin-1 to immunogenic dendritic cells reduces phosphorylation and activity of the protein-tyrosine kinase Pyk2, an effect that may also contribute to reduced migration of this subset. In a murine lymphedema model, galectin-1(-/-) animals had increased numbers of migratory dendritic cells in draining lymph nodes, specifically dendritic cells with an immunogenic phenotype. These findings define a novel role for galectin-1 in inhibiting tissue emigration of immunogenic, but not tolerogenic, dendritic cells, providing an additional mechanism by which galectin-1 can dampen immune responses.
在炎症过程中，树突状细胞从炎症组织穿过淋巴管内皮进入淋巴脉管系统，并迁移至局部淋巴结以启动免疫反应。然而，调节树突状细胞从组织中逸出并穿过淋巴管内皮的过程尚未明确界定。哺乳动物凝集素半乳糖凝集素-1在炎症组织的血管内皮细胞中高度表达，并且已被证明可调节免疫细胞进入炎症组织。在此，我们表明半乳糖凝集素-1在人淋巴管内皮细胞中也高度表达，并且半乳糖凝集素-1在细胞外基质中的沉积选择性地调节特定人类树突状细胞亚群的迁移。半乳糖凝集素-1的存在抑制免疫原性树突状细胞穿过细胞外基质和淋巴管内皮细胞的迁移，但对耐受性树突状细胞的迁移没有影响。两种树突状细胞群体上主要的半乳糖凝集素-1反受体是细胞表面粘蛋白CD43；免疫原性树突状细胞和耐受性树突状细胞之间CD43的核心2 O-糖基化差异似乎导致了半乳糖凝集素-1对迁移的不同作用。半乳糖凝集素-1与免疫原性树突状细胞的结合降低了蛋白酪氨酸激酶Pyk2的磷酸化和活性，这一作用也可能导致该亚群迁移减少。在小鼠淋巴水肿模型中，半乳糖凝集素-1基因敲除（galectin-1(-/-)）动物引流淋巴结中迁移性树突状细胞的数量增加，特别是具有免疫原性表型的树突状细胞。这些发现确定了半乳糖凝集素-1在抑制免疫原性而非耐受性树突状细胞的组织逸出中的新作用，为半乳糖凝集素-1减弱免疫反应提供了一种额外机制。
