The human interleukin-2 receptor is being studied to understand critical components of the T cell immune response in normal and neoplastic cells. When T-cells are activated by antigen or mitogenic lectin, both IL-2 and IL-2 receptor expression are induced. IL-2 and IL-2 receptors regulate the magnitude and duration of the T-cell immune response, based on the amount of IL-2 produced, the levels of receptors expressed, and the time course of each of these events. Whereas a low level of intermediate affinity IL-2 receptors are expressed on resting cells, following antigen stimulation, both high and low affinity IL-2 receptor expression is potently induced. Three chains of the IL-2 receptor are now known to exist, namely IL- 2Ralpha, and IL-2Rbeta, and IL-2Rgamma. IL-2Ralpha and IL-2Rbeta have been cloned and this lab was the first to analyze the promoters of each of these genes. In the past year, the group has made major advances. (1) A new enhancer has been identified in the IL-2Ralpha 5' regulatory region. (2) The critical cis-acting elements in the IL-2Rbeta promoter have been delineated for the first time and two regions with enhancer activity have been characterized. (3) Major progress has been made in identifying transcription factors responsible for the regulation of expression of both the IL-2Ralpha and IL-2Rbeta chain genes. (4) One transcription factor (NF-kappaB), which is critical for IL-2Ralpha expression in HTLV-I transformed cells, has been studied. HTLV-I is a virus which caused adult T-cell leukemia, an agressive leukemia prevalent in Japan, the Caribbean basin, parts of Africa, and the Southeastern United States. In particular, a region of NF-kappaB p50 and p65 which is critical for DNA binding has been delineated. This region contains an interesting motif spanning a critical cysteine which is present in all kappaB binding proteins. In NF- kappaB family proteins, the cysteine mediates NF-kappaB binding sensitivity to oxidation/reduction. Such knowledge may be critical in eventually designing therapeutic agents to act as agonists or antagonists of kappaB regulated genes. These findings therefore are critical not only to an understanding of IL-2 receptor gene regulation but also extend to the regulation of other T-cell activation genes.
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