Microbiota regulation of intestinal eosinophils

摘要

Abstract Food allergy is characterized by aberrant immune activation in response to an innocuous food antigen and affects 5-8% of the US population. The current standard of care remains limited to allergen avoidance, demonstrating the need for new therapeutic avenues. One promising approach would be to control the initiation of the allergic inflammatory response mediated by T helper 2 (Th2) cells. In food allergy, Th2 cells are induced by antigen- presenting dendritic cells (DCs) in the gut, which in turn are activated by intestinal eosinophils, an innate immune cell type associated with type 2 immunity. Therefore, regulation of intestinal eosinophils represents a promising point at which to intervene at the beginning of an allergic response. Although the gut contains the largest eosinophil population in the body, understanding of the signals controlling their accumulation and function remains limited. An environmental signal likely to regulate intestinal eosinophils is the microbiota, which is critical in shaping intestinal immune cells. Interestingly, microbiota disruption either in germ-free (GF) mice or with antibiotic treatment in both mice and humans is also associated with exacerbation and increased incidence of food allergy, but the mechanism is not entirely clear. I hypothesize that the microbiota regulates intestinal eosinophils and their function in food allergy. My proposed mechanistic studies of intestinal eosinophil regulation by the microbiota will culminate in a peanut antigen food allergy model to determine how this environmental factor controls eosinophil function in disease. Elucidating how gut-specific signals influence eosinophils would improve understanding of their biology and identify novel therapeutic targets for these cells in food allergy. Additionally, the Training Plan developed alongside this Research Plan will provide a blueprint to prepare me for a successful academic career. With the support of my Sponsor and Co-Sponsor in the innovative and collaborative environment at Harvard, this fellowship will enable me to be well poised for an eventual independent position in mucosal immunology.