A crucial role for T-bet in selectin ligand expression in T helper 1 (Th1) cells.
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 beta1,6 N-acetylglucosaminyltransferase I (C2GlcNAcT-I), but no differences in levels of alpha 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.
Underhill
Greg H
GH
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 303 E Chicago Ave, Chicago, IL 60611, USA.
Zisoulis
Dimitrios G
DG
Kolli
K Pallav
KP
Ellies
Lesley G
LG
Marth
Jamey D
JD
Kansas
Geoffrey S
GS
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D005434:Flow Cytometry; D005647:Fucosyltransferases / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D016695:Glycosyltransferases / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019087:Selectins / Q000276:immunology / Q000378:metabolism*; D012799:Sialyltransferases / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; D000098815:T-bet Transcription Factor
D008024:Ligands; D019087:Selectins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D018664:Interleukin-12; D016695:Glycosyltransferases; D005647:Fucosyltransferases; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase