International Immunology, Vol. 15, No. 10, pp. 1149-1160,
October 2003
© 2003 Japanese Society for Immunology
Identification of cooperative monomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-
promoter
1 Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, MO 63110, USA 2 Present address: School of Biotechnology and Bioengineering, Kangwon National University, 92-1, Hyoja2-Dong, Chuncheon, Kangwon-Do 200-701, Korea
Correspondence to: K. M. Murphy, Department of Pathology and Immunology, Washington University School of Medicine, Box 8118, 660 S. Euclid Avenue, St Louis, MO 63110, USA. E-mail: murphy@immunology.wustl.edu
Transmitting editor: J. P. Allison
The T-box transcription factor T-bet has been reported to augment the activity of IFN-
reporter constructs and to be required for CD4+, but not CD8+, T cell production for IFN-. Despite these observations, the precise sequence targets of T-bet within the IFN- locus have not been identified and the nature of T-bet’s role in selectively augmenting IFN- production in CD4+ T cells has not been elucidated. As an initial step in this process, we examined the basis of T-bet-dependent augmentation of IFN- reporter constructs to identify specific targets of this factor within the IFN- locus. Deletion of previously proposed TDB and TRU elements left T-bet-induced IFN- reporter activity unchanged, suggesting the existence of additional T-bet-responsive elements. We identified several additional monomeric Brachyury consensus elements within the proximal IFN- promoter that operate cooperatively to increase both constitutive and stimulated promoter activity. The most proximal of these Brachyury elements is most significant quantitatively in mediating T-bet-dependent promoter augmentation. Mutation of this with any of the other Brachyury elements leads to a near eradication of T-bet-dependent promoter activation. The identification of these individual monomeric Brachyury-binding sites within the IFN- locus should facilitate the in vivo analysis of the function of T-bet in the lineage- and background-dependent requirement for T-bet in IFN- gene regulation.
Keywords: IFN-, T-bet, transcription factor
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