Il2 Receptors--molecular Regulation

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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 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. Moreover, in addition to a previously reported IL-2 response element in the 5' regulatory region of the IL-2Ra gene, the existence of another important regulatory element, denoted PRRIV, was reported. This element is highly conserved in humans and mice and is located in the first intron. This element is regulated by Stat5 and HMG-I(Y) proteins. Together with the upstream IL-2 response element, the intronic element controls IL-2-mediated regulation of the IL-2Ra gene. In a collaborative study, it was also reported that the HTLV-1 p12I protein can enhance Stat5 activation and diminish the IL-2 requirement for proliferation of primary human peripheral blood mononuclear cells. Together, these studies substantially enhance our understanding of the basis of IL-2R expression and Stat5-dependent gene regulation.