IL-7 receptor signaling in lymphopoiesis

Duke University, Durham NC

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Abstract

Interleukin 7 (IL-7) has been demonstrated to provide signals via the IL-7 receptor which are required at many stages of lymphocyte development. IL-7 receptor is composed of two different cytokine receptor subunits;the 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, such as 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. On the other hand, IL-7 plays a critical role in regulation of EBF expression at an early phase of B cell development in adult bone marrow. 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. Although progress has been made in identifying the intracellular mediators of IL-7 receptor signaling that regulate these developmental processes, significant gaps remain. The specific aims for the next 5 year term are as follows: 1) to determine the role of IL-7 in maintenance of B cell potential in pre-proB/CLP2 cells;2) to determine importance of 414-441 a.a. region of IL-7 receptor alpha in B cell development;and 3) to clarify the role of IL-7R and Flt3 in EBF expression during B cell development. The goal of this project is to elucidate the signaling pathways downstream of IL-7 receptor, which drive specific steps in lymphocyte development, and to determine the genes involved in this process.