Interleukin 7 (IL-7) has been demonstrated to provide signals, via the IL-7 receptor, which are required at many stages of lymphocyte development and play a role in maintaining homeostasis of T cells in the periphery as well. IL-7 receptor is composed of two different cytokine receptor subunits, IL-7 receptor alpha chain and the common gamma chain. These two subunits are shared with other cytokine receptors: IL-7 receptor alpha chain is also a subunit of the functional thymic stromal lymphopoiesis receptor, while common gamma chain is a component of functional receptor complexes for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. The developmental processes governed by IL-7 receptor signaling include initiation of cell proliferation, protection from apoptotic cell death, and the induction of lineage-specific events (i.e., gene rearrangement in antigen receptor loci). We have previously shown that cell survival signaling mediated by IL-7-driven upregulation of an anti-apoptotic protein, Bcl-2, is important for T cell development. We have also demonstrated that Bcl-2 expression in peripheral T cells is directly regulated by IL-7 receptor signaling. Dysfunction of IL-7 receptor subunits (either IL-7 receptor alpha or common gamma chains) causes profound immunodeficiency in both humans and mice, highlighting the central role IL-7 plays in lymphopoiesis. Conversely, supra-physiological levels of IL-7 lead to dramatic alterations in mouse lymphocyte development, culminating in the malignant transformation of lymphocytes. Although progress has been made in identifying the intracellular mediators of IL-7 receptor signaling that regulate these developmental and transforming processes, significant gaps remain. We will focus not only on positive signal transduction pathways, but also on the negative regulation of activated signaling via IL-7 receptors. We will also investigate the role of IL-7 receptor signaling in vivo by introducing IL-7 receptor alpha mutants. The goal of this project is to elucidate the signaling pathways downstream of IL-7 receptor that drive specific steps in lymphocyte development.
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