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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056123-03
Application #
7012240
Study Section
Immunobiology Study Section (IMB)
Program Officer
Macchiarini, Francesca
Project Start
2004-02-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$300,762
Indirect Cost
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Chung, Eva; Hsu, Chia-Lin; Kondo, Motonari (2011) Constitutive MAP kinase activation in hematopoietic stem cells induces a myeloproliferative disorder. PLoS One 6:e28350
Kondo, Motonari (2010) Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors. Immunol Rev 238:37-46
Lai, Anne Y; Watanabe, Akiko; O'Brien, Tommy et al. (2009) Pertussis toxin-sensitive G proteins regulate lymphoid lineage specification in multipotent hematopoietic progenitors. Blood 113:5757-64
Ueda, Yoshihiro; Cain, Derek W; Kuraoka, Masayuki et al. (2009) IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia. J Immunol 182:6477-84
Kikuchi, Kazu; Kasai, Hirotake; Watanabe, Akiko et al. (2008) IL-7 specifies B cell fate at the common lymphoid progenitor to pre-proB transition stage by maintaining early B cell factor expression. J Immunol 181:383-92
Lai, Anne Y; Kondo, Motonari (2008) T and B lymphocyte differentiation from hematopoietic stem cell. Semin Immunol 20:207-12
Hsu, Chia-Lin; Kikuchi, Kazu; Kondo, Motonari (2007) Activation of mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK) signaling pathway is involved in myeloid lineage commitment. Blood 110:1420-8
Lai, Anne Y; Kondo, Motonari (2007) Identification of a bone marrow precursor of the earliest thymocytes in adult mouse. Proc Natl Acad Sci U S A 104:6311-6
Jiang, Qi; Coffield, V McNeil; Kondo, Motonari et al. (2007) TSLP is involved in expansion of early thymocyte progenitors. BMC Immunol 8:11
Kikuchi, Kazu; Kondo, Motonari (2006) Developmental switch of mouse hematopoietic stem cells from fetal to adult type occurs in bone marrow after birth. Proc Natl Acad Sci U S A 103:17852-7

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