The overall goal of this proposal is to understand the cellular and molecular factors that regulate dendritic cell activation in response to aeroallergens. Dendritic cells have been shown to control immune responses both in the priming of naive CD4 T cells and in the re-elicitation of effector CD4 T cell responses at the site of antigen entry. Dendritic cells are not only important in CD4 T cell activation but in regulating differentiation of CD4 T cells into Th2 and Th1 cells. In this application, we question how dendritic cells become activated to aeroallergens without apparent microbial sequences and how dendritic cells induce preferential Th2 responses. We hypothesize that the Toll-like receptor signaling in response to inhaled antigen is essential for both Th1 and Th2 priming and that the dose of pathogen associated molecular pattern (PAMP), in this case lipopolysaccharide, influences dendritic cells to become either Th2- or Th1-inducing. Furthermore, we speculate that IL-13 plays an essential role in amplifying Th2 responses to inhaled antigen by sustaining dendritic cell activation. In this way, innate immune signals are required to initiate adaptive immune responses, but once initiated, adaptive immune signals via IL-13 can provide activation signals to maintain Th2 responses. We will test this hypothesis in two specific aims: 1) To determine the mechanism by which low dose lipopolysaccharide induces Th2 priming following inhaled antigen. 2) To determine the role of IL-13 in Th2 priming. Understanding the factors that regulate the initiation of Th2 responses to aeroallergens will shed light on possible environmental factors influencing the dramatic increase in atopic asthma in the past 15 years. ? ?
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