A crucial role for T-bet in selectin ligand expression in T helper 1 (Th1) cells

Abstract

Proinflammatory T helper 1 (Th1) cells express high levels of carbohydrate ligands for the endothelial selectins, but the molecular basis for this phenotype is incompletely understood. We document here a significant role in selectin ligand formation for the recently described Th1 transcription factor T-bet. Th1 cells generated from T-bet ؊/؊ mice showed significantly lower levels of ligands for both E-selectin and P-selectin, compared with wild-type (WT) Th1 cells. Enforced expression of T-bet in WT Th0 cells only modestly up-regulated P-selectin ligands and had no effect on E-selectin ligands. To define a mechanism for the defects observed in T-bet ؊/؊ mice, we examined expression of glycosyltransferases involved in selectin ligand biosynthesis. T-bet ؊/؊ Th1 cells expressed significantly lower levels of core 2 ␤1,6 N-acetylglucosaminyltransferase I (C2GlcNAcT-I), but no differences in levels of ␣ 2,3-sialyltransferase IV (ST3Gal-IV). Further, we show that T-bet is responsible for the signal transducer and activator of transcription 4 (Stat4)-independent increase in Th1 cells of fucosyltransferase VII (FucT-VII). We also identify ST3Gal-VI, which is thought to play an important role in E-and P-selectin ligand formation, as an interleukin 12 (IL-12)

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

“…To analyze whether CD43 and CD44 also function as E-selectin ligands on NK cells, we pretreated DX5 ϩ CD90 Ϫ NK cells with a robust protease, bromelain, before lysate preparation. With the exception of ESL-1, an E-selectin ligand characteristically localized in the Golgi (34), bromelain digestion cleaves all cell surface E-selectin glycoprotein ligands on leukocytes (20,33,37). By flow cytometry, we first confirmed that bromelain treatment eliminated PSGL-1, CD43 and CD44 expression (data not shown).…”

“…Leukocyte E-and P-selectin ligands engage in low-affinity, Ca 2ϩ -dependent binding interactions with E-and P-selectin constitutively expressed on dermal postcapillary venules and initiate their recruitment into inflamed skin (1,(3)(4)(5)(6)(7). Functional activity of these ligands is dependent on the expression on sialo-fucosylated carbohydrate moieties synthesized by ␣2,3 sialyltransferase IV (32,37,38) and FT4/7 (9, 10). Identification of authentic leukocyte E-and P-selectin ligands has been vigorously investigated, as the implication of their neutralization may provide a means for management of chronic inflammatory conditions, such as atopic/allergic dermatitis and psoriasis, and cutaneous lymphomas.…”

Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes

“…This finding prompted us earlier to suggest that T-bet would play an important role in FUT7 transcription and sialyl Lewis X expression in T lymphocytes (3). This proposal was supported by a recent study reporting a significant reduction of selectin ligand activity in T-bet deficient mice (25). The transfection of T-bet gene alone to cultured lymphoid cells, however, failed to confer appreciable selectin ligand expression either in a murine (26) or human system (see below), and the exact role played by T-bet in regulation of FUT7 transcription remains obscure.…”

Activation of Murine CD4+ and CD8+ T Lymphocytes Leads to Dramatic Remodeling ofN-Linked Glycans

“…The additional increased expression of fucosyl-and sialyltransferases in Th1 cells promotes synthesis of the selectin ligand sialyl-Lewis X (NeuAc␣2-3Gal␤1-4[Fuca1-3]GlcNAc), while Th2 helper cells lack sialyl-Lewis X sequences because a key fucosyltransferase, Fuc-T VII, is not expressed. Such differential glycosylation accounts for the selectin-mediated recruitment of CD4 Th1 cells to sites of inflammation (11)(12)(13)(14)(15)(16)(17).…”