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A Novel Endothelial L-Selectin Ligand Activity in Lymph Node Medulla That Is Regulated by (1,3)-Fucosyltransferase-IV

Christine M'Rini¹, Guiying Cheng¹, Colleen Schweitzer¹, Lois L. Cavanagh^1,2, Roger T. Palframan^1,2, Thorsten R. Mempel¹, Richard A. Warnock^1,3, John B. Lowe⁴, Elizabeth J. Quackenbush^1,5 and Ulrich H. von Andrian^1,2

¹ CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115
² Department of Pathology, Harvard Medical School, Boston, MA 02115
³ Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University Medical School, Stanford, CA 94305
⁴ Howard Hughes Medical Institute and Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
⁵ Merck Research Laboratories, Division of Pharmacology, Merck and Company, Rahway, NJ 07065

Address correspondence to Ulrich H. von Andrian, CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115. Phone: (617) 278-3130; Fax: (617) 278-3190; email: uva{at}cbr.med.harvard.edu

Lymphocytes home to peripheral lymph nodes (PLNs) via high endothelial venules (HEVs) in the subcortex and incrementally larger collecting venules in the medulla. HEVs express ligands for L-selectin, which mediates lymphocyte rolling. L-selectin counterreceptors in HEVs are recognized by mAb MECA-79, a surrogate marker for molecularly heterogeneous glycans termed peripheral node addressin. By contrast, we find that medullary venules express L-selectin ligands not recognized by MECA-79. Both L-selectin ligands must be fucosylated by (1,3)-fucosyltransferase (FucT)-IV or FucT-VII as rolling is absent in FucT-IV+VII^-/- mice. Intravital microscopy experiments revealed that MECA-79–reactive ligands depend primarily on FucT-VII, whereas MECA-79–independent medullary L-selectin ligands are regulated by FucT-IV. Expression levels of both enzymes paralleled these anatomical distinctions. The relative mRNA level of FucT-IV was higher in medullary venules than in HEVs, whereas FucT-VII was most prominent in HEVs and weak in medullary venules. Thus, two distinct L-selectin ligands are segmentally confined to contiguous microvascular domains in PLNs. Although MECA-79–reactive species predominate in HEVs, medullary venules express another ligand that is spatially, antigenically, and biosynthetically unique. Physiologic relevance for this novel activity in medullary microvessels is suggested by the finding that L-selectin–dependent T cell homing to PLNs was partly insensitive to MECA-79 inhibition.

Key Words: homing • intravital microscopy • leukocyte adhesion • leukocyte rolling • vascular addressin

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