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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3867-3873.
Prepublished online as a Blood First Edition Paper on August 11, 2005; DOI 10.1182/blood-2005-03-0984.
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IMMUNOBIOLOGY
A crucial role for T-bet in selectin ligand expression in T helper 1 (Th1) cells
Greg H. Underhill,
Dimitrios G. Zisoulis,
K. Pallav Kolli,
Lesley G. Ellies,
Jamey D. Marth, and
Geoffrey S. Kansas
From the Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and the Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA.
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)–regulated, T-bet–dependent gene. These data show that T-bet controls selectin ligand formation in Th1 cells via control of expression of multiple key enzymes in response to IL-12 signaling and establishes an independent transcriptional pathway for control of Th1 cell traffic.
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