Abstract
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.
Highlights
Lymphocyte recirculation through lymph nodes and Peyer’s patches is important for detection of foreign antigens by the immune system and subsequent processes that neutralize these molecules
The binding of L-selectin-IgM chimeric protein was almost entirely lost on the luminal side of high endothelial venules (HEV) derived from peripheral and mesenteric lymph nodes under the conditions where strong binding was observed in HEV of wild-type mice (Fig. 1, C and F)
The abluminal expression of L-selectin ligand is present on Peyer’s patches of wild-type mice (Fig. 1E). Consistent with these findings, MECA-79 antigen is drastically reduced in GlyCAM-1 isolated from LSST⌬ mice, and only 34% of MECA-79 antigen was detected compared with GlyCAM-1 from wild-type mice (Fig. 1I)
Summary
Lymphocyte recirculation through lymph nodes and Peyer’s patches is important for detection of foreign antigens by the immune system and subsequent processes that neutralize these molecules. GlyCAM-1 Derived from LSST⌬ Mice Still Contains Significant Amounts of 6-Sulfo sLex—The above results suggest that levels of L-selectin ligand in peripheral and mesenteric lymph nodes should be significantly reduced, and only a small fraction of GlyCAM-1 O-glycans should contain 6-sulfo sLex. Because no structural information was available on GlyCAM-1 from LSST⌬ mice in the previous report (23), we analyzed O-glycans attached to GlyCAM-1 isolated from peripheral and mesenteric lymph nodes cultured in the presence of [3H]galactose as described previously (Fig. 2A) (20).
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