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

Tenbrock K, Kyttaris VC, Ahlmann M, Ehrchen JM, Tolnay M, Melkonyan H, Mawrin C, Roth J, Sorg C, Juang YT and Tsokos GC
Source: J Immunol
Publication Date: (2005)
Issue: 175(9): 5975-5980
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
PBMC, human
Species: human
Tissue Origin: blood
Nucleofector® I/II/2b
Systemic lupus erythematosus T cells display decreased amounts of TCR zeta mRNA that results in part from limited binding of the transcriptional enhancer Elf-1 to the TCR zeta promoter. We have identified a new cis-binding site for the cAMP response element (CRE) modulator (CREM) on the TCR zeta promoter, centered on the -390 nucleotide. Transfection of T cells with an antisense CREM alpha plasmid reduced the binding of CREM to the TCR zeta promoter, as shown by chromatin and reporter chromatin immunoprecipitation assays, and enhanced the production of TCR zeta mRNA and protein. Mutagenesis of the -390 CRE site prevented the binding of CREM to the TCR zeta promoter. The mechanism of CREM-mediated repression appears to be chromatin dependent, because antisense CREM promotes the acetylation of histones on the TCR zeta promoter. Finally, we established an enhanced binding of CREM to the TCR zeta-chain promoter in systemic lupus erythematosus cells compared with control T cells. Our studies demonstrate that CREM alpha binds to the TCR zeta promoter and repress its activity.