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

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.