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J. Biol. Chem., Vol. 279, Issue 4, 3058-3067, January 23, 2004

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Core 2 Branching 1,6-N-Acetylglucosaminyltransferase and High Endothelial Venule-restricted Sulfotransferase Collaboratively Control Lymphocyte Homing^*

Nobuyoshi Hiraoka, Hiroto Kawashima, Bronislawa Petryniak¶, Jun Nakayama||, Junya Mitoma, Jamey D. Marth**, John B. Lowe¶, and Minoru Fukuda

From the Glycobiology Program, Cancer Research Center, The Burnham Institute, La Jolla, California 92037, the ^¶Howard Hughes Medical Institute, Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, the ^||Department of Pathology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan, and the ^**Howard Hughes Medical Institute, Division of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093

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 1,6-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.

Received for publication, October 10, 2003 , and in revised form, October 28, 2003.

^* The work was supported by Grants PO1CA71932 (to M. F. and J. B. L.), DK48247 (to J. D. M.), and R37CA33000 (to M. F.) from the National Institutes of Health, by Howard Hughes Investigator Awards (to J. B. L. and J. D. M.), and by Priority Area 14082201 (to J. N.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors equally contributed to the work.

To whom correspondence should be addressed: The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3144; Fax: 858-646-3193; E-mail: minoru{at}burnham.org.

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