Cells of the innate immune system, antigen-presenting cells (APCs), are critical to the initiation of both naive and memory T cell responses to antigens. Dendritic cells (DCs) are the most competent of the APCs, and it is DCs that dictate whether the outcome of a T cell's encounter with antigen will be tolerance or immunity. In the naive state, DCs are widely distributed in lymphoid and non-lymphoid organs. For example, the respiratory tract contains an extensive network of DCs to monitor the pulmonary environment. The goal of this project is to characterize the antigen-presenting environment in pre- and post-natal life, with the focus on defining factors that dictate whether exposure to allergen in early life induces T cell sensitization or tolerance. The thinking is that in certain circumstances, T cell sensitization can occur in utero or in early post-natal life and that factors responsible for these circumstances have increased in the past 20 years. It has been proposed that this could explain the increased incidence of asthma and other inflammatory diseases. The challenge for scientists is to identify factors that control this process, with the ultimate goal of developing therapeutic strategies to reverse the progressive increase in disease. It is controversial whether exposure to antigen in early life results in sensitization or tolerance upon secondary exposure to the same antigen, and the cell types responsible for these life-long changes in immunity and their mechanisms of action remain to be identified. Our studies will concentrate on DCs as they direct the T cell responses to antigen throughout life, presumably including the pre- and post-natal period, the long term consequences of which will be defined in studies proposed in this application. In addition, we will define how maternal immune responsiveness via maternal transfer of certain Ig isotypes and antigen impacts on the functional capacity of DCs and the development of immune responsiveness in offspring. We have established murine models that will allow us to assess how the route of antigen administration, timing of the antigen exposure, and environment dictate DC function to ultimately result in T cell sensitization or tolerance in early life. Identification of critical factors in this process will enhance the possibility of altering disease outcomes using DCs as therapeutic immunoregulators, or in the design of vaccination strategies for susceptible individuals. To this end, we propose to:
AIM 1. Determine the capacity of dendritic cells to present antigen and initiate T cell responses in pre- and post-natal life.
AIM 2. Determine the role of maternal-derived immune complexes on dendritic cell function in pre- and post-natal life.
AIM 3. Determine the effect of perinatal antigen presentation on long-term T cell immunity.
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