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The Cyclic AMP Response Element Modulator Regulates Transcription of the TCR -Chain¹

Klaus Tenbrock^2,*,,, Vasileios C. Kyttaris^,¶, Martina Ahlmann^*,, Jan Mauno Ehrchen, Mate Tolnay^||, Harutyun Melkonyan, Christian Mawrin, Johannes Roth^*,, Clemens Sorg, Yuang-Taung Juang and George C. Tsokos

^* Department of Pediatrics, Division of Rheumatology, University Hospital, Institute of Experimental Dermatology, and Interdisciplinary Center for Clinical Research, Research Group 5, University of Muenster, Muenster, Germany; Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910; ^¶ Section of Rheumatology, Washington Hospital Center, Washington, D.C. 20010; and ^|| Division of Monoclonal Antibodies, Food and Drug Administration, Rockville, MD 20857

Systemic lupus erythematosus T cells display decreased amounts of TCR mRNA that results in part from limited binding of the transcriptional enhancer Elf-1 to the TCR promoter. We have identified a new cis-binding site for the cAMP response element (CRE) modulator (CREM) on the TCR promoter, centered on the –390 nucleotide. Transfection of T cells with an antisense CREM plasmid reduced the binding of CREM to the TCR promoter, as shown by chromatin and reporter chromatin immunoprecipitation assays, and enhanced the production of TCR mRNA and protein. Mutagenesis of the –390 CRE site prevented the binding of CREM to the TCR promoter. The mechanism of CREM-mediated repression appears to be chromatin dependent, because antisense CREM promotes the acetylation of histones on the TCR promoter. Finally, we established an enhanced binding of CREM to the TCR -chain promoter in systemic lupus erythematosus cells compared with control T cells. Our studies demonstrate that CREM binds to the TCR promoter and repress its activity.

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