The α(1,3)Fucosyltransferase Fuc-TVII Controls Leukocyte Trafficking through an Essential Role in L-, E-, and P-selectin Ligand Biosynthesis

Abstract

alpha(1,3)Fucosylated oligosaccharides represent components of leukocyte counterreceptors for E- and P-selectins and of L-selectin ligands expressed by lymph node high endothelial venules (HEV). The identity of the alpha(1,3)fucosyltransferase(s) required for their expression has been uncertain, as has a requirement for alpha(1,3)fucosylation in HEV L-selectin ligand activity. We demonstrate here that mice deficient in alpha(1,3) fucosyltransferase Fuc-TVII exhibit a leukocyte adhesion deficiency characterized by absent leukocyte E- and P-selectin ligand activity and deficient HEV L-selectin ligand activity. Selectin ligand deficiency is distinguished by blood leukocytosis, impaired leukocyte extravasation in inflammation, and faulty lymphocyte homing. These observations demonstrate an essential role for Fuc-TVII in E-, P-, and L-selectin ligand biosynthesis and imply that this locus can control leukocyte trafficking in health and disease.

Fucosyltransferase VII-Deficient Mice with Defective E-, P-, and L-Selectin Ligands Show Impaired CD4+ and CD8+ T Cell Migration into the Skin, but Normal Extravasation into Visceral Organs

“…Mice lacking FucTVII Ϫ/Ϫ show a deficiency of E-, P-, and Lselectin ligand activity (10,11). In FucTVII Ϫ/Ϫ mice, the fraction of rolling leukocytes is markedly reduced (26), and these mice show leukocytosis with increased counts of blood neutrophils, lymphocytes, monocytes, and eosinophils.…”

“…The generation of the FucTVII Ϫ/Ϫ mice has previously been described in detail (10). Founder mice were backcrossed into C57BL/6 mice for more than six generations.…”

“…These mice have previously been shown to exhibit compromised leukocyte extravasation using a chemical peritonitis model, as well as reduced cell numbers in their lymph nodes, suggesting a leukocyte-trafficking defect (10). Deficiency of E-and P-selectin ligands on Th1 and T cytotoxic 1 lymphocytes was demonstrated to annul trafficking of these T cells to inflamed cutaneous sites, as demonstrated by the absence of cutaneous hypersensitivity to 2,4-dinitrofluorobenzene in ␣-1,3-fucosyltransferase VII (FucTVII) Ϫ/Ϫ mice (11).…”

“…Mice genetically manipulated to lack expression of fucosyltransferase VII were found to be deficient in E-, P-, and L-selectin ligand activity (10). These mice have previously been shown to exhibit compromised leukocyte extravasation using a chemical peritonitis model, as well as reduced cell numbers in their lymph nodes, suggesting a leukocyte-trafficking defect (10).…”

Neutrophil-Epithelial Interactions

“…94 Similarly, mice lacking specific fucosyltransferases (IV and VII) have the same deficits in neutrophil adhesion as those found in selectin-deficient mice. 95,96 Despite the known importance of fucosylation in PMN extravasation, the role of fucosylated glycans during PMN epithelial interactions and PMN function in general have not been characterized to date. It was recently shown that antibody-mediated ligation of Lewis X [Galb1-4(Fuca1-3) GlcNAcb-R, Le x ] on neutrophils results in increased neutrophil adhesive interactions.…”