The goal of this research program is to test the hypothesis that dendritic cells (DCs) of the gastro intestinal tract process lumenal antigens by Fc-epsilon-RI-IgE mediated uptake, thereby affecting the intestinal inflammatory response and type I hypersensitivity. Fc-epsilon-RI, the high affinity IgE Fc-receptor, is a multimeric immune recognition receptor that binds IgE through a monovalent epitope in its alpha chain. Antigen-induced crosslinking of the IgE-Fc-epsilon-RI complex causes cell activation via the signaling subunits of the receptor (Fc-epsilon-RI-beta and a dimer of the common gamma chain). A unique feature of Fc-epsilon- RI is its cell type- and species-specific expression pattern. In mice, the receptor is expressed only as a heterotetramer (alpha, beta, and two gamma chains) on mast cells and basophils. In humans, Fc-epsilon-RI assembles as a heterotetramer on mast cells and basophils, but additionally also as a heterotrimer lacking the beta subunit. Uniquely, the human heterotrimeric form of Fc-epsilon-RI is expressed on antigen presenting cells, including DCs in the intestine. Surface expression of the receptor correlates with allergic diseases, and controls IgE-mediated cell activation during the allergic response. Unlike other multimeric immune recognition receptors, surface expression is regulated at the level of co-translational assembly of subunits in the endoplasmic reticulum; but the mechanism of regulation remains unknown.
Aim 1 will elucidate structural features of individual Fc-epsilon-RI subunits that dictate receptor assembly and thus surface expression of Fcepsilon- RI complexes.
Aim 2 will determine if the human trimeric Fc-epsilon-RI functions on DCs or macrophages to present antigen via IgE-mediated uptake pathways. This set of experiments will use Fcepsilon- RI-expressing murine cells that allow us to study functional consequences of receptor-mediated antigen presentation for T cell activation in the MHC class II and the MHC class I pathways.
Aim 3 will investigate IgE-mediated intestinal immune responses in vivo using a transgenic animal conditionally expressing the human alpha-chain of Fc-epsilon-RI on DCs.
| Lexmond, Willem S; Goettel, Jeremy A; Lyons, Jonathan J et al. (2016) FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy. J Clin Invest 126:4030-4044 |
| Platzer, Barbara; Elpek, Kutlu G; Cremasco, Viviana et al. (2015) IgE/Fc?RI-Mediated Antigen Cross-Presentation by Dendritic Cells Enhances Anti-Tumor Immune Responses. Cell Rep : |
| Goettel, Jeremy A; Biswas, Subhabrata; Lexmond, Willem S et al. (2015) Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. Blood 125:3886-95 |
| Platzer, B; Baker, K; Vera, M P et al. (2015) Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites. Mucosal Immunol 8:516-32 |
| Platzer, Barbara; Stout, Madeleine; Fiebiger, Edda (2014) Antigen cross-presentation of immune complexes. Front Immunol 5:140 |
| Wurbel, Marc-André; Le Bras, Severine; Ibourk, Mouna et al. (2014) CCL25/CCR9 interactions are not essential for colitis development but are required for innate immune cell protection from chronic experimental murine colitis. Inflamm Bowel Dis 20:1165-76 |
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| Baker, Kristi; Rath, Timo; Lencer, Wayne I et al. (2013) Cross-presentation of IgG-containing immune complexes. Cell Mol Life Sci 70:1319-34 |
| Platzer, Barbara; Dehlink, Eleonora; Turley, Shannon J et al. (2012) How to connect an IgE-driven response with CTL activity? Cancer Immunol Immunother 61:1521-5 |
| Bannert, Christina; Bidmon-Fliegenschnee, Bettina; Stary, Georg et al. (2012) Fc-epsilon-RI, the high affinity IgE-receptor, is robustly expressed in the upper gastrointestinal tract and modulated by mucosal inflammation. PLoS One 7:e42066 |
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