The α(1,3)fucosyltransferases FucT-IV and FucT-VII Exert Collaborative Control over Selectin-Dependent Leukocyte Recruitment and Lymphocyte Homing

The first step of leukocyte extravasation, leukocyte rolling, is mediated by E-, P-, and L-selectins. Mice deficient for α-1,3-fucosyltransferase VII (FucTVII)−/− are characterized by deficiency of E-, P-, and L-selectin ligand activity. This model system was used to evaluate the role of the interactions of selectins with their ligands in T and B cell responses. In the present study, FucTVII−/− mice showed reduced CD4+ T cell-mediated contact hypersensitivity reactions of the ears to FITC as well as reduced CD8+ T cell-mediated delayed-type hypersensitivity reactions of the footpads against lymphocytic choriomeningitis virus infection. As Langerhans cell migration to local lymph nodes as well as CD4+ and CD8+ T cell induction were found to be normal, the afferent arm of these reactions was not impaired. The reduced inflammatory reactions of the skin were due to inefficient lymphocyte extravasation into the skin. In contrast, extravasation of CD4+ and CD8+ T cells into visceral organs, such as the ovaries or the brain, was not impaired in FucTVII−/− mice. Elimination of vaccinia virus and of lymphocytic choriomeningitis virus from ovaries and brain, as well as elimination of tumor cells from several visceral organs was normal. Thus, interactions of selectins with their ligands are important for lymphocyte homing into the skin, but not for lymphocyte extravasation into visceral organs.

Section: Discussionsupporting

confidence: 89%

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

Erdmann¹,

Scheidegger²,

Koch³

et al. 2002

“…The expression of protease-resistant E-selectin ligand activity on NK cells may elicit compensatory inflammatory activity in allergic CHS models performed in PSGL-1 Ϫ/Ϫ CD43 Ϫ/Ϫ mice (26,27). Indeed, deficiencies of both FT4 and 7 are required for complete blunting of leukocyte E-selectin ligand formation and inflammatory activity (7,9) and FT4 preferentially generates sialyl Lewis X moieties and E-selectin-binding determinants on glycolipids. These findings and others support our contention that protease-resistant E-selectin glycolipid ligand(s) is a key component of NK cellular activity (28).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, E-and P-selectin ligands are critical for T cell trafficking to inflamed skin (4,8) and, together, are characteristically referred to as "skin-homing receptors." In vivo models of T cell-mediated inflammation reveal that E-and P-selectin ligand function and skin-tropic behavior on T cells are dependent on ␣1,3 fucosyltransferases IV and VII (FT4/7) (7,9,10). These enzymes are responsible for generating sialyl Lewis X moieties on T cell membrane protein and lipid scaffolds, conferring ligand activity and the skin-homing designation of leukocytes (11)(12)(13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

Skin-Homing Receptors on Effector Leukocytes Are Differentially Sensitive to Glyco-Metabolic Antagonism in Allergic Contact Dermatitis

Gainers

Descheny

Barthel

et al. 2007

T cell recruitment into inflamed skin is dependent on skin-homing receptor binding to endothelial (E)- and platelet (P)-selectin. These T cell receptors, or E- and P-selectin ligands, can be targeted by the metabolic fluorosugar inhibitor, 4-F-GlcNAc, to blunt cutaneous inflammation. Compelling new data indicate that, in addition to T cells, NK cells are also recruited to inflamed skin in allergic contact hypersensitivity (CHS) contingent on E- and P-selectin-binding. Using a model of allergic CHS, we evaluated the identity and impact of NK cell E-selectin ligand(s) on inflammatory responses and examined the oral efficacy of 4-F-GlcNAc. We demonstrated that the predominant E-selectin ligands on NK cells are P-selectin glycoprotein ligand-1 and protease-resistant glycolipids. We showed that, unlike the induced E-selectin ligand expression on activated T cells upon exposure to Ag, ligand expression on NK cells was constitutive. CHS responses were significantly lowered by orally administered 4-F-GlcNAc treatment. Although E-selectin ligand on activated T cells was suppressed, ligand expression on NK cells was insensitive to 4-F-GlcNAc treatment. These findings indicate that downregulating effector T cell E- and P-selectin ligand expression directly correlates with anti-inflammatory efficacy and provides new insight on metabolic discrepancies of E-selectin ligand biosynthesis in effector leukocytes in vivo.

“…C57BL/6 mice possessing a homozygous deletion of the FucT-IV gene, the FucT-VII gene, and both FucT-IV and FucT-VII genes were used and have previously been described in detail (20). Phenotypically these mice were healthy, fertile, and had no growth abnormality in appearance or body weight (14).…”

Section: Knockout Animalsmentioning

confidence: 99%

“…selectin ligand expression in the murine kidney using an E-selectin/IgM chimera to identify FucT-dependent expression of selectin ligands (20). We then investigated the pathophysiologic role of FucTs in an established murine model of renal IRI (21).…”

mentioning

confidence: 99%

Pathophysiological Contributions of Fucosyltransferases in Renal Ischemia Reperfusion Injury

Burne

Rabb

2002

Ischemia reperfusion injury (IRI) is a major cause of delayed graft function. Recent studies have shown that selectins play an important role in IRI. Selectins bind to sialylated and fucosylated sLex receptors, and two enzymes, fucosyltransferase IV (FucT-IV) and VII (FucT-VII), are important in the function of these receptors. We hypothesized that fucosyltransferase (FucT) enzymes were important pathophysiologic mediators of renal IRI. We therefore evaluated renal IRI in mice deficient in FucT-IV, FucT-VII, and both FucT-IV and FucT-VII and compared their renal function, tubular injury, selectin ligand expression, and neutrophil infiltration to those in wild-type control mice. Bilateral 30-min renal IRI was performed, and the results demonstrated that mice deficient in both FucT-IV/FucT-VII were significantly protected from renal IRI at 24 and 48 h compared with wild-type control mice. FucT-IV-deficient mice showed only modest protection from renal injury at 24 h. However, FucT-VII-deficient mice had similar injury as wild-type mice. Histological analysis of kidney tissue postischemia revealed that mice deficient in both FucT-IV and FucT-VII had significantly reduced tubular injury compared with wild-type mice. Selectin ligand expression increased postischemia in wild-type, but not FucT-IV/FucT-VII-deficient, mice. Neutrophil infiltration in postischemic kidneys of FucT-IV/FucT-VII-deficient mice was also attenuated. These data demonstrate that fucosyltransferases are important in the pathogenesis of renal IRI and are potential therapeutic targets.