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

Heart, Lung, And Blood Institute

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Abstract

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 some of these cytokines, particularly the activation of STAT proteins (signal transducers and activators of transcription), and the mechanism by which they regulate cytokine/STAT target genes.[unreadable] [unreadable] Previously the group demonstrated that IL-7 receptor alpha chain expression is negatively regulated by IL-2. Although some information was 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 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 reported that unexpectedly GABP was also a critical regulator of B cell development, acting in part by regulating Pax5 and Pax5 target genes. The group also reported that GABP and PU.1 control maturation stage-specific regulation of megaakaryopoiesis. Moreover, it was also found that GABP regulates expression of the gene encoding a serine-threonine kinase, denoted KIS, that phosphorylates p27Kip1, a cyclin-dependent kinase inhibitor, as well as cell migration and cell cycle progression.[unreadable] [unreadable] The group has continued studies of regulation of gamma chain family cytokines and their receptors. Given the previous demonstration by the group that IL-21 regulates expression of Blimp-1, the molecular basis for this observation has also been pursued. The group has also continued studies of STAT proteins, including the importance of STAT tetramerization for gene regulation.[unreadable] [unreadable] The group also investigated the regulation of the FoxP3 gene that controls the development and function of regulatory T cells, demonstrating and reporting the existence of a CREB/ATF-dependent enhancer and the role for DNA methylation in the control of expression of this gene.[unreadable] [unreadable] These findings enhance our understanding of mechanisms controlling expression of genes that regulate the immune response.