Investigating the Effect of IgE and IgE-Mediated Mast Cell Activation on Dendritic Cell Function in Peanut Allergic Mice

Abstract

Dendritic cells (DCs) are key cellular players in the body's innate immune surveillance of the extracellular environment and initiation of adaptive immune responses. They play a pivotal role in scavenging, capturing and processing a number of antigens, including food proteins, to induce cellular T cell responses. Given their importance in the establishment of allergic sensitization, DCs have repeatedly been appreciated as the drivers of type 2 responses that trigger the production of IgE, a critical component of hypersensitivity reactions. Normally found at low titers, this antibody binds to its high affinity receptor Fc R1 on mast cells and basophils, causing the release of preformed mediators that are capable of inducing severe anaphylactic responses. However, very little is understood about the effect of IgE-mediated mast cell activation on DC function, and whether IgE plays a direct or indirect role in modulating immune sensitization. We aimed to address this enigma by studying the function and migration of DCs during sensitization and challenge in an animal model of peanut food allergy. Utilizing IgE-sufficient and -deficient F709 mice, which possess a disinhibited form of the IL-4 receptor due to a targeted mutation in the IL-4R immunoreceptor tyrosine-based inhibitory motif (ITIM), we assessed the movement of different dendritic cell subsets from the gut to the mesenteric lymph nodes (mLNs) after repeated enteral peanut ingestion. We demonstrate that IgE plays a role in the migration of plasmacytoid DCs (pDCs), CD103+, and CX3CR1+ DCs to the mesenteric lymph nodes. This is predicted after the increase in all three populations at certain time points in the mLN's after a six-week sensitization and challenge protocol. Conversely, this phenotype is abolished in IgE-deficient F709 mice, revealing an interesting role of IgE in preserving and supporting the migration of these dendritic cell populations from the gut to the mesenteric lymph nodes. To further validate our findings of the effect of IgE on dendritic cell function we cultured BMDC's and stimulated them under different conditions with and without anti peanut IgE and peanut. We observe an affect of IgE in dendritic cells, as seen by the changes in costimulatory and inhibitory markers. Collectively, our findings suggests a unique role for IgE in modulating dendritic cell function, and their consequent migration to the mesenteric lymph nodes.