The-180 site of the IL-2 promoter is the target of CREB/CREM binding in T cell anergy

Anergic T cells display a marked decrease in their ability to produce IL-2 even in the presence of optimal TCR and costimulatory signals. Using IL-2 e nhancer/promoter-driven reporter constructs, we have previously identified a region that appears to be a target for cis transcriptional repression in anergy. This region of the promoter, which shares partial homology with a c onsensus AP-l-binding sequence, is located about -180 bp from the transcrip tional start site. In the present study, we demonstrate that cAMP response element-binding protein/cAMP response element modulator (CREB/CREM), activa ting transcription factor-2/c-Jun, and Jun-Jun/Oct complexes bind to this s ite. However, the induction of anergy by prolonged stimulation through the TCR led to an increase in binding of only the CREB/CREM complex. Furthermor e, the level of binding of this complex appeared to be up-regulated in both resting and restimulated anergic T cells. Finally, an IL-2 promoter-driven reporter construct that contained a mutation that specifically reduced the binding of the CREB/CREM complex displayed a decreased ability to be affec ted by anergy, while a construct that contained a mutation that decreased t he binding of the Jun-Jun/Oct complex was still susceptible to anergy, Thes e findings suggest that the -180 region of the IL-2 promoter is the target of a CREB/CREM transcriptional inhibitor that contributes to the repression of IL-2 production in T cell anergy.