CREB, ATF AND AP-1 TRANSCRIPTION FACTORS REGULATE IFN-γ SECRETION BY HUMAN T CELLS IN RESPONSE TO MYCOBACTERIAL ANTIGEN1

• Published in: The Journal of immunology (1950) Vol. 181; no. 3; pp. 2056 - 2064
• Main Authors: Samten, Buka, Townsend, James C., Weis, Steven E., Bhoumik, Anindita, Klucar, Peter, Shams, Homayoun, Barnes, Peter F.
• Format: Journal Article
• Language: English
• Published: 01-08-2008
• ISSN: 0022-1767; 1550-6606

IFN-γ production by T cells is pivotal for defense against many pathogens, and the proximal promoter of IFN-γ, −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 CREB/ATF and AP-1 transcription factors on the proximal promoter of IFN-γ in human T cells stimulated with
M. 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-γ 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-γ proximal promoter in live antigen-activated T cells. Inhibition of ATF-2 activity in T-cells with a dominant-negative ATF-2 peptide or with siRNA markedly reduced the expression of IFN-γ and decreased the expression of CREB and c-Jun. These findings suggest that CREB, ATF-2 and c-Jun are recruited to the IFN-γ proximal promoter, and upregulate IFN-γ transcription in response to microbial antigen. In addition, ATF-2 controls expression of CREB and c-Jun during T-cell activation.