The human interleukin-2 receptor is being studied to understand critical components of the T cell immune response in normal and neoplastic cells. Following T-cell activation, IL-2 and IL-2 receptors are induced; the magnitude and duration of the T-cell immune response is controlled by the amount of IL-2 produced, the levels of receptors expressed, and the time course of these events. Three chains of the IL-2 receptor exist, IL-2Ra, IL-2Rb, and gc, with IL-2Ra and IL-2Rb being significantly regulated at the level of transcription. The group has focused primarily on the types of signals induced by IL-2, particularly the activation of STAT proteins (signal transducers and activators of transcription), and the mechanism by which they regulate the IL-2Ra gene. Stat5a and Stat5b are two closely related proteins with >90% amino acid identity that are activated by IL-2. An important issue is whether these closely related proteins are redundant or distinctive in their actions. To attempt to clarify this issue, Stat5a and Stat5b transgenic mice have been generated to reconstitute the knockout mice. A major role for Stat5 proteins in regulating CD8+ T cell homeostasis was discovered. Stat5a and Stat5b are adjacent genes located in a head-to-head orientation. Aspects of similarities vs. differences in regulation of these genes is being studied. Two IL-2 response elements in the IL-2Ra gene were previously reported, one in the 5' regulatory region and the other in the first intron. This second regulatory element, denoted PRRIV, was reported to be a TCR response element as well. This element is highly conserved in humans and mice and is located in the first intron. This element is regulated not only by Stat5 and HMG-I(Y) proteins but also by NFAT and AP1 sites. Together with the upstream elements, the intronic element controls IL-2-mediated and TCR-mnediated regulation of the IL-2Ra gene. Together, these studies substantially enhance our understanding of the basis of IL-2R expression and Stat5-dependent gene regulation.
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