Novel CD28-responsive enhancer activated by CREB/ATF and AP-1 families in the human interleukin-2 receptor alpha-chain locus

The interaction of interleukin-2 (IL-2) with its receptor (IL-2R) criticall y regulates the T-cell immune response, and the alpha chain CD25/IL-2R alph a is required for the formation of the high-affinity receptor. Tissue-speci fic, inducible expression of the IL-2R alpha gene is regulated by at least three positive regulatory regions (PRRI, PRRII, and PRRIII), but none respo nded to CD28 engagement in gene reporter assays although CD28 costimulation strongly amplifies IL-2R alpha gene transcription. By DNase I hypersensiti vity analysis, we have identified a novel TCR-CD3- and CD28-responsive enha ncer (CD28rE) located 8.5 kb 5' of the IL-2R alpha gene. PRRIV/CD28rE conta ins a functional CRE/TRE element required for CD28 signaling. The T-cell-sp ecific, CD28-responsive expression of the IL-2R alpha gene appears controll ed through PRRIV/CD28rE by cooperation of CREB/ATF and AP-1 family transcri ption factors.