The basis for IL-2-induced IL-2 receptor a chain gene regulation: Importance of two widely separated IL-2 response elements

The interleukin-2 receptor alpha (IL-2R alpha) chain is an essential compon ent of high-affinity IL-2 receptors. Accordingly, lL-2R alpha expression he lps to regulate T cell growth and other lymphoid functions. Lineage-restric ted and activation-dependent IL-2R alpha transcription is controlled by thr ee upstream positive regulatory regions (PRRs). We now describe an addition al IL-2 response element, PRRIV, within intron 1, in humans and mice. PRRIV activity requires GAS motifs that bind Stat5 proteins and additional upstr eam HMG-I(Y) binding sites. Moreover, IL-2 induces the binding of HMG-I(Y), Stat5a, and Stat5b in vivo to PRRIV and PRRIII, which also functions as an IL-2 response element. Thus, the IL-2 inducibility of the lL-2Ra gene is u nexpectedly mediated by two widely separated regulatory Stat5-dependent ele ments, located both upstream and downstream of the transcription initiation sites.