title: Differential regulation and impact of fucosyltransferase VII and core 2 β1,6-N-acetyl-glycosaminyltransferase for generation of E-selectin and P-selectin ligands in murine CD4+ T cells.
abstract: Ligands for E-selectin and P-selectin (E-lig and P-lig) are induced on CD4+ T cells upon differentiation into effector T cells. Glycosyltransferases, especially α 1,3-fucosyltransferase VII (FucT-VII) and core 2 β1,6-N-acetyl-glycosaminyltransferase I (C2GlcNAcT-I), are critical for their synthesis. We here analysed the signals that control the expression of E-lig, P-lig and mRNA coding for FucT-VII and C2GlcNAcT-I. In line with previous reports, we found that P-lig expression correlates with the regulation of C2GlcNAcT-I, whereas E-lig expression can occur at low levels of C2GlcNAcT-I mRNA but requires high FucT-VII mRNA expression. Interestingly, the two enzymes are regulated by different signals. Activation-induced C2GlcNAcT-I up-regulation under permissive (T helper type 1) conditions was strongly reduced by cyclosporin A (CsA), suggesting the involvement of T-cell receptor-dependent, calcineurin/NFAT-dependent signals in combination with interleukin-12 (IL-12) -mediated signals in the regulation of C2GlcNAcT-I. In contrast, expression of FucT-VII mRNA was not significantly inhibited by CsA. Interleukin-4 inhibited the expression of FucT-VII but IL-2 and IL-7 were found to support induction of FucT-VII and E-lig. E-selectin, P-selectin and their ligands initially appeared to have rather overlapping functions. These findings however, unravel striking differences in the regulation of E-lig and P-lig expression, dictated by the dominance of FucT-VII and C2GlcNAcT-I, respectively, and their dependency on signals from either promiscuous or homeostatic cytokines (FucT-VII) or a strong T-cell receptor signal in combination with inflammatory cytokines in case of C2GlcNAcT-I.
authors.affiliation: Experimentelle Rheumatologie, Deutsches Rheuma-Forschungszentrum, Berlin, Germany.
authors.forename: Micha F
authors.initials: MF
authors.lastname: Schroeter
authors.forename: Boris A
authors.initials: BA
authors.lastname: Ratsch
authors.forename: Jeanette
authors.initials: J
authors.lastname: Lehmann
authors.forename: Ria
authors.initials: R
authors.lastname: Baumgrass
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.forename: Uta
authors.initials: U
authors.lastname: Syrbe
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D019040:E-Selectin / Q000378:metabolism*; D005647:Fucosyltransferases / Q000235:genetics / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D007376:Interleukin-2 / Q000502:physiology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000502:physiology*; D019007:P-Selectin / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology
chemical_list: D019040:E-Selectin; D007376:Interleukin-2; D008024:Ligands; D019007:P-Selectin; D011948:Receptors, Antigen, T-Cell; D016572:Cyclosporine; D005647:Fucosyltransferases; D017351:N-Acetylglucosaminyltransferases; C514210:fucosyltransferase VII, mouse; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase