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Secretion by Human T Cells in Response to Mycobacterial Antigen1
,
* Center for Pulmonary and Infectious Disease Control,
Department of Microbiology and Immunology, and
Department of Medicine, University of Texas Health Center, Tyler, TX 75708;
Department of Internal Medicine, University of North Texas Health Sciences Center, Fort Worth, TX 76107; and
¶ Signal Transduction Program, Burnham Institute for Biomedical Research, La Jolla, CA 92037
IFN-
production by T cells is pivotal for defense against many pathogens, and the proximal promoter of IFN-, –73 to –48 bp upstream of the transcription start site, is essential for its expression. However, transcriptional regulation mechanisms through this promoter in primary human cells remain unclear. We studied the effects of cAMP response element binding protein/activating transcription factor (CREB/ATF) and AP-1 transcription factors on the proximal promoter of IFN- in human T cells stimulated with Mycobacterium tuberculosis. Using EMSA, supershift assays, and promoter pulldown assays, we demonstrated that CREB, ATF-2, and c-Jun, but not cyclic AMP response element modulator, ATF-1, or c-Fos, bind to the proximal promoter of IFN- upon stimulation, and coimmunoprecipitation indicated the possibility of interaction among these transcription factors. Chromatin immunoprecipitation confirmed the recruitment of these transcription factors to the IFN- proximal promoter in live Ag-activated T cells. Inhibition of ATF-2 activity in T cells with a dominant-negative ATF-2 peptide or with small interfering RNA markedly reduced the expression of IFN- and decreased the expression of CREB and c-Jun. These findings suggest that CREB, ATF-2, and c-Jun are recruited to the IFN- proximal promoter and that they up-regulate IFN- transcription in response to microbial Ag. Additionally, ATF-2 controls expression of CREB and c-Jun during T cell activation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health (A1063514) and the Margaret E. Byers Cain Chair for Tuberculosis Research (to P.F.B.).
2 Address correspondence and reprint requests to Dr. Buka Samten, Center for Pulmonary and Infectious Disease Control, University of Texas Health Science Center, 11937 U.S. Highway 271, Tyler, TX 75708. E-mail address: buka.samten{at}uthct.edu
3 Current address: Baylor Institute for Immunology Research, 3434 Live Oak Street, Dallas, TX 75204.
4 Abbreviations used in this paper: CREB, cAMP response element binding protein; ATF, activating transcription factor; wt-CRE, wild-type CREB consensus binding site; mt-CRE, mutant CREB consensus binding site; CREM, cAMP response element modulator; CRE, cAMP response element; AP-1, activating protein 1.
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  X. Wang, P. F. Barnes, K. M. Dobos-Elder, J. C. Townsend, Y.-t. Chung, H. Shams, S. E. Weis, and B. Samten ESAT-6 Inhibits Production of IFN-{gamma} by Mycobacterium tuberculosis-Responsive Human T Cells J. Immunol., March 15, 2009; 182(6): 3668 - 3677. [Abstract] [Full Text] [PDF]
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