IL-2 Family Cytokines and their Receptors--Molecular Reg

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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 genes 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. Moreover, we have previously shown the oncogenic potential of these Stat proteins. Having last year shown that some of the regulated genes are located in "clusters", the group this year extended its work of an IL-2 regulated gene, IL-2Ra, and reported the identification of a Smad-dependent TGFbeta response element in this gene. 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 was some information available 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 previously 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 additionally had previously generated mice with diminished levels of GABPalpha by a gene-trap methodology. Embryos with diminished expression of GABPalpha exhibited markedly decreased numbers of thymocytes and lower IL-7Ra expression on those cells. In the past year, we have substantially extended our studies of GABP and its role in lymphoid development. Finally, related to its study of the IL-21 system, the group made major progress in characterizing the basis for regulation of the IL-21R gene, reporting that the gene exhibits a biphasic activation pattern in response to TCR stimulation and characterizing Sp1 as a critical transcription factor whose induction and desphosphorylation was involved in this process. These findings enhance our understanding of mechanisms controlling expression of genes that regulate the immune response, with potential therapeutic implications in the future.