Journal Article

Interaction of GATA-3/T-Bet Transcription Factors Regulates Expression of Sialyl Lewis X Homing Receptors on Th1/Th2 Lymphocytes

Santamaria-Babi, Luis F., Osada, Hirotaka, Kannagi, Reiji, Chen, Guo-Yun

2006

Overview

Selectin-dependent cell adhesion mediates inflammatory extravasation and routine homing of lymphocytes. Most resting peripheral T lymphocytes lack expression of sialyl Lewis X, the carbohydrate ligand for selectins, and are induced to strongly express it upon activation. T helper 1 (Th1) cells are known to more preferentially express sialyl Lewis X as compared with T helper 2 (Th2) cells upon activation. The molecular basis for this preferential expression, however, has not been elucidated to date. Here we show that the gene for fucosyltransferase VII (FUT7), the rate-limiting enzyme for sialyl Lewis X synthesis, is a unique example of the human genes with binding sites for both GATA-3 and T-bet, two opposing factors for Thl and Th2 development, and is regulated transcriptionally by a balance of the two interacting transcription factors. T-bet promotes and GATA-3 represses FUT7 transcription. Our results indicated that T-bet interferes with the binding of GATA-3 to its target DNA, and also that GATA-3 significantly interferes with the binding of T-bet to the FUT7 promoter. T-bet has a binding ability to GATA-3, CBP/P300, and Sp1 to form a transcription factor complex, and GATA-3 regulates FUT7 transcription by phosphorylationdependently recruiting histone deacetylase (HDAC)-3/HDAC-5 and by competing with CBP/P300 in binding to the N terminus of T-bet. Suppression of GATA-3 activity by dominant-negative GATA-3 or repressor of GATA (ROG) was necessary to attain a maximum expression of FUT7 and sialyl Lewis X in human T lymphoid cells. These results indicate that the GATA-3/T-bet transcription factor complex regulates the cell-lineage-specific expression of the lymphocyte homing receptors.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Antibodies / Biological Sciences / Cell Line / Cell lines / Chlorocebus aethiops / COS Cells / Fucosyltransferases - genetics / Fucosyltransferases - metabolism / GATA transcription factors / GATA3 Transcription Factor - genetics / GATA3 Transcription Factor - metabolism / Gene Expression Regulation, Enzymologic / HL-60 Cells / Humans / Jurkat Cells / Lymphocytes / Models, Biological / Natural killer cells / Oligosaccharides - biosynthesis / Promoter regions / Promoter Regions, Genetic / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Sialyl Lewis X Antigen / T lymphocytes / T-Box Domain Proteins - genetics / T-Box Domain Proteins - metabolism / Th1 Cells - metabolism / Th2 Cells - metabolism / Transcription factors / Transcription, Genetic / Transcriptional regulatory elements / Transfection