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.
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