Recent developments have suggested important regulatory functions of mast cells, including presentation of antigen to T cells and induction of IgE production by B cells. The recent and unexpected finding that FcepsilonRI is expressed on human langerhans cells, monocytes and eosinophils have suggested that FcepsilonRI may have much broader functions than previously believed. The primary objective of this proposal is to test the hypothesis that FcepsilonRI plays a central role in the regulatory functions of mast cells and the Specific Aims are the following: 1. The establishment of the role of mast cells in antigen presentation. The effectiveness of mast cells in antigen presentation to T cells via the Fcepsilon RI pathway will be examined. The hypothesis that mast cells can direct T cells to differentiate preferentially to the Th2 subset will be tested and comparison will be made with other antigen presenting cells. The involvement of co-stimulatory molecules in this process will be determined. The role of FcepsilonRI in antigen presentation will also be confirmed by in vivo experiments. 2. The establishment of regulatory role of FcepsilonRI in induction of IgE synthesis by B cells. The ability of murine mast cells to induce IgE synthesis by B cells will be examined. Cell surface molecules that are involved in mast cell/B cell interactions will be identified. The role of FcepsilonRI in this process will be confirmed by comparing mast cells from FcepsilonRI-deficient mice with those from their normal littermates as well as by using soluble FcepsilonRI as an inhibitor. The relationship between mast cell activation and induction of IgE synthesis will be investigated. The role of mast cell FcepsilonRI in antibody responses to soluble antigens will be evaluated. 3. The establishment of the role of FcepsilonRI in allergic airway inflammation. By using FcepsilonRI-deficient mice, we will determine whether FcepsilonRI-mediated mast cell activation is critical for allergen-induced airway inflammation. The influence of mast cell activation on differential Th1/Th2 responses will be investigated. The ability of lung mst cells to present antigens to T cells will be evaluated. The ability of lung mast cells to induce B cell IgE synthesis will also be assessed. A fuller understanding of the functions of mast cells, including those mediated by FcepsilonRI, should facilitate the development of drugs, targeted at inhibition of mast cell activity, for the treatment of allergic inflammation.
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