Stromal cells of the thymus and bone marrow play important roles in lymphocyte development through mechanisms that involve cell contact and the elaboration of cytokines. A novel cytokine, termed thymic stroma- derived lymphopoietin (TSLP), and a corresponding receptor for this cytokine have been identified based on the ability of TSLP to promote B lymphopoiesis in vitro. Studies proposed in this application will provide basic information regarding several related aspects of this novel cytokine. First, new information regarding the cellular sources of TSLP and the distribution of receptors for this cytokine among different populations of lymphoid cells will be generated. Second, several assays will be used to determine the responsiveness of defined populations of immature B and T cells to exogenous TSLP and examine the effect of exogenous TSP or TSLP deprivation on T and B lymphopoiesis in vitro and in vivo. Third, because of preliminary data indicating that the IL7R contributes to the functional TSLP receptor, the hypothesis that the action of TSLP, which is highly expressed in the thymus, may have functional overlap with IL7 will be tested. Such a relationship may account for the disparities in the severity of symptoms observed in IL7-/- and IL7R-/- mice and the differential sensitivity of B and T lymphopoiesis to the lack of IL7. Fourth, based on the autoimmune phenotype exhibited by transgenic mice over-expressing TSLP, they hypothesis that altered levels of TSLP may lead to disruption of mechanisms that normally maintain self- tolerance will be tested. The basic information regarding TSLP production, target cells responding to this cytokine, and the functional consequences of altered levels of TSLP on lymphocyte development and function may lead to the identification of the human homologue and may be of clinical relevance. These studies could ultimately lead to therapeutic modalities that may be beneficial in reversing the effects of primary or acquired immunodeficiencies affecting lymphocyte production and may be useful in designing approaches to retard age-related decline of lymphopoiesis. Understanding the mechanism(s) whereby overexpression of TSLP leads to the development of autoimmune symptoms may lead to a new paradigm to study the pathogenesis of autoimmunity.
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