The broad, long-term objectives of this proposal are to understand how lymphokine synthesis is regulated in human CD4+ T cells, and how CD4+ T cells with restricted cytokine profiles develop in immune responses. The development of such cells with distinct cytokine profiles in response to antigen may be a critical and pivotal point in the regulation of immune responses. In as much as IL-4 is absolutely required for IgE synthesis, and as it upregulates the synthesis of itself and of IL-5, the development and activation of CD4+ T cells secreting large quantities of IL-4 may be a fundamental problem that operates in atopic diseases, and control of IL-4 production may be key in the regulation of allergic disease. The purpose of this proposal is to: 1. examine the immunologic parameters that influence the development of IL-4 synthesis (and of other lymphokines) in CD4+ T cells, determining the influence of exogenous cytokines, antigen concentration, antigen presenting cell (APC) type, and APC costimulator molecules. 2. determine how lymphokine regulation differs in allergic and nonallergic individuals. Cytokine synthesis will be examined at the bulk population level as well as at the single cell level in response to different types and forms of antigen. Since we have data in mice indicating that APC from high-IgE responder strains regulate lymphokine synthesis differently from those of low-IgE responder strains, we will examine APC from allergic and nonallergic individuals to determine how APC actively regulate cytokine synthesis in T cells. In addition, we will use mAb to CD3 and to specific costimulator molecules to dissect the role of costimulator molecules in this developmental process. The division of CD4+ T cells into subsets with differing and restricted cytokine profiles is of fundamental importance in the regulation of immune responses. Knowledge of the precise mechanisms that regulate the development of CD4+ T cell subsets, and of how such regulation differs in allergic versus nonallergic individuals is critical in understanding and treating diseases such as allergy, autoimmune disease, susceptibility to infection, or cancer, which may stem from the development of CD4+ T cells with inappropriate cytokine profiles.
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