IL-2 Receptors--Molecular Regulation of Receptor Express

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The human interleukin-2 receptor and related cytokine/cytokine receptor systems are 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. gc is a shared chain also used by the receptors for IL-4, IL-7, IL-9, IL-15, and IL-21, and is the protein that is mutated in XSCID. 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 and other IL-2 induced genes. In the accompanying annual report, it is summarized that we have reported the characterization of a large number of genes that are regulated by gc dependent cytokines. Many of these appear to be dependent on two closely-related Stat5 proteins, denoted Stat5a and Stat5b, and we have previously demonstrated that these two proteins critically control IL-2 receptor alpha chain gene regulation by binding to two widely separated IL-2 response elements. The genes regulated by IL-2 were studied in greater detail, both by DNA array and SAGE methodology. In addition to identifying a large number of new genes, it was discovered and reported that some of the genes occur in "clusters". Regarding IL-2Ra gene regulation itself, the group made progress in the identification of a TGFbeta response element in the IL-2Ra gene, which now has been characterized and reported. Stat5a and Stat5b are two closely related proteins with >90% amino acid identity that are activated by IL-2. The genes encoding Stat5a and Stat5b are adjacent and the genes are located in a head-to-head orientation. 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 were generated to reconstitute the knockout mice. In addition, aspects of similarities vs. differences in regulation of these genes are being studied. The phenotype of Stat5a and Stat5b transgenic mice was striking. Our studies revealed that these proteins play a major role in the regulation of CD8+ T cell homeostasis and these findings were reported. Moreover, as the mice aged, they developed thymic lymphoblastic lymphoma, even though they did not exhibit a constitutively activated Jak-STAT pathway. Previously, we and others demonstrated that a constitutively activated Jak-STAT pathway correlates with and perhaps is causal in the development of certain malignancies. In the associated report, it is noted that we previously demonstrated that IL-7 receptor alpha chain expression is potently negatively regulated by IL-2. Although there is some information regarding the basis for regulation of the IL-7 receptor in B cells, essentially nothing was known in T cells. In B cells, an Ets family transcription factor, PU.1, is critical for control of the gene. We defined and reported the transcription initiation site for the gene, and discovered that the same Ets binding site that binds PU.1 in B cells is also essential for IL-7Ra expression in T cells, but that in T cells, the critical factor is GA binding protein (GABP). We generated mice with diminished levels of GABPalpha by a gene-trap methodology. Embryos with diminished expression of GABPalpha exhibited marked diminished numbers of thymocytes and diminished IL-7Ra on those cells. In contrast fetal liver B cells had normal levels of IL-7R expression. These data indicate that differential regulation of IL-7Ra in distinct lymphoid lineages is achieved at least in part by differential recruitment of factors to the same GGAA motif. These latter findings were all reported in the past year. Finally, related to its study of IL-21, the group made major progress in characterizing the basis for regulation of the IL-21 gene and these findings were reported. Moreover, much has been learned about T-cell receptor mediated increases in the expression of the receptor for IL-21. These findings enhance our understanding of mechanisms controlling expression of genes that regulate the immune response, with potential therapeutic implications in the future.