Core 2 branching β1,6-N-acetylglucosaminyltransferase and high endothelial venule-restricted sulfotransferase collaboratively control lymphocyte homing
Core 2 branching β1,6-N-acetylglucosaminyltransferase and high endothelial venule-restricted sulfotransferase collaboratively control lymphocyte homing
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DOI：
10.1074/jbc.m311150200
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发表时间：
2004-01-23
影响因子：
4.8
通讯作者：
Fukuda, M
中科院分区：
文献类型：
--
作者：
Hiraoka, N;Kawashima, H;Fukuda, M
L-选择素通过促进淋巴细胞粘附于次级淋巴器官的高内皮微静脉（HEV）上表达的碳水化合物配体来介导淋巴细胞归巢。以前的研究表明，L-选择素配体磺基转移酶（LSST）在核心2分支和MECA-79阳性延伸的核心1 O-聚糖上形成6-磺基唾液酸刘易斯x（sLe（x）），但LSST和核心2 β 1，6-N-乙酰葡糖胺转移酶-1（Core 2GlcNAcT）阐述的HEV配体的化学性质和作用尚未确定。在本研究中，我们产生了LSST缺陷的突变小鼠，并表明LSST基因单独失活仅导致淋巴细胞归巢至外周淋巴结的部分损伤和外周淋巴结中淋巴细胞计数的中度减少，尽管含有6-磺基sLe（x）的L-选择素配体在HEV中减少。相比之下，LSST/Core 2GlcNAcT双无效小鼠表现出显著减少的淋巴细胞归巢和减少的淋巴细胞计数，这是由于相对于LSST或Core 2GlcNAcT单无效小鼠，HEV L-选择素反受体上的6-磺基sLe（x）显著降低。此外，在显示慢性炎症的非肥胖糖尿病小鼠的唾液腺中形成的HEV样结构中观察到LSST和Core 2GlcNAcT转录物的诱导。这些结果表明，LSST和Core 2GlcNAcT协同合成淋巴细胞归巢所需的HEV特异性L-选择素配体，并表明LSST和Core 2GlcNAcT在慢性炎症期间的淋巴细胞运输中起关键作用。
L-selectin mediates lymphocyte homing by facilitating lymphocyte adhesion to carbohydrate ligands expressed on high endothelial venules (HEV) of the secondary lymphoid organs. Previous studies demonstrated that L-selectin ligand sulfotransferase ( LSST) forms 6-sulfo sialyl Lewis x (sLe(x)) on both core 2 branch and MECA-79-positive extended core 1 O-glycans, but the chemical nature and roles of HEV ligands elaborated by LSST and core 2 beta1,6-N-acetylglucosaminyltransferase-1 (Core2GlcNAcT) have been undefined. In the present study, we have generated mutant mice with deficient LSST and show that inactivation of LSST gene alone leads to only partial impairment of lymphocyte homing to peripheral lymph nodes and moderate reduction in lymphocyte counts in the peripheral lymph nodes, despite the fact that L-selectin ligands that contain 6-sulfo sLe(x) are reduced at HEV. By contrast, LSST/Core2GlcNAcT double null mice exhibited a markedly reduced lymphocyte homing and reduced lymphocyte counts as a result of significantly decreased 6-sulfo sLe(x) on HEV L-selectin counterreceptors, relative to LSST-or Core2GlcNAcT-single null mice. Moreover, induction of LSST and Core2GlcNAcT transcripts was observed in HEV-like structure formed in the salivary gland of the non-obese diabetic mouse, which displays chronic inflammation. These results indicate that LSST and Core2GlcNAcT cooperatively synthesize HEV-specific L-selectin ligands required for lymphocyte homing and suggest that LSST and Core2GlcNAcT play a critical role in lymphocyte trafficking during chronic inflammation.