The factors that control B cell tolerance of self antigens remains unclear. One critical aspect of B cell tolerance is the development of a functional immune system, which includes the proper expression and function of cytokines and their cognate receptors, hi lymphopoiesis, interleukin (IL)-7 has been shown to be a critical component of both T and B cell development. Recently, a new cytokine, thymic stromal lymphopoietin (TSLP), has been identified and shown to influence both T and B lymphopoiesis. TSLP and IL-7 share a receptor subunit, but differentially regulate B cell development. Engagement of the TSLP receptor complex triggers a signal transduction pathway that differs from that of IL-7, which may account for the differences in biological outcome. Also, TSLP has been shown to be involved in aspects of allergic inflammation, another feature that sets it apart from IL-7. The experiments in this proposal will focus on several aspects of TSLP biology, including a detailed structure/function analysis of the TSLP receptor complex. The role of TSLP in regulating B cell development and function will be examined in several ways, using mice that express inducible TSLP transgenes, allowing the expression of the transgene to be controlled both spatially and temporally. Previous work has shown that mice with elevated levels of TSLP display auto antibodies and develop autoimmune-like symptoms. We will dissect the mechanism underlying TSLP-mediated breakdown of B cell tolerance. These experiments will provide important new information regarding the role of TSLP in lymphopoiesis, and lay the foundation of a more detailed analysis of the cytokine networks in lymphoid development and in the their role in regulating B cell tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI044259-09S1
Application #
8087359
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Peyman, John A
Project Start
2010-07-01
Project End
2011-02-28
Budget Start
2010-07-01
Budget End
2011-02-28
Support Year
9
Fiscal Year
2010
Total Cost
$179,968
Indirect Cost
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
Iseki, Masanori; Omori-Miyake, Miyuki; Xu, Whitney et al. (2012) Thymic stromal lymphopoietin (TSLP)-induced polyclonal B-cell activation and autoimmunity are mediated by CD4+ T cells and IL-4. Int Immunol 24:183-95
Ziegler, Steven F; Artis, David (2010) Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 11:289-93
Ziegler, Steven F (2010) The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr Opin Immunol 22:795-9
Larson, Ryan P; Zimmerli, Simone C; Comeau, Michael R et al. (2010) Dibutyl phthalate-induced thymic stromal lymphopoietin is required for Th2 contact hypersensitivity responses. J Immunol 184:2974-84
Miazgowicz, Michael M; Headley, Mark B; Larson, Ryan P et al. (2009) Thymic stromal lymphopoietin and the pathophysiology of atopic disease. Expert Rev Clin Immunol 5:547-556
Iyoda, Masayuki; Hudkins, Kelly L; Becker-Herman, Shirly et al. (2009) Imatinib suppresses cryoglobulinemia and secondary membranoproliferative glomerulonephritis. J Am Soc Nephrol 20:68-77
Headley, Mark B; Zhou, Baohua; Shih, Weihui X et al. (2009) TSLP conditions the lung immune environment for the generation of pathogenic innate and antigen-specific adaptive immune responses. J Immunol 182:1641-7
Lee, Hai-Chon; Headley, Mark B; Iseki, Masanori et al. (2008) Cutting edge: Inhibition of NF-kappaB-mediated TSLP expression by retinoid X receptor. J Immunol 181:5189-93
Zhou, Baohua; Headley, Mark B; Aye, Theingi et al. (2008) Reversal of thymic stromal lymphopoietin-induced airway inflammation through inhibition of Th2 responses. J Immunol 181:6557-62
Astrakhan, Alexander; Omori, Miyuki; Nguyen, Thuc et al. (2007) Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development. Nat Immunol 8:522-31

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