Gastrointestinal tissue-adapted eosinophils in health and disease

The National Institute of Allergy and Infectious Diseases awarded The Regents of the University of Colorado, doing business as University of Colorado-Denver, $771,983 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate gastrointestinal tissue-adapted eosinophils in health and disease.

The project, titled "Gastrointestinal Tissue-Adapted Eosinophils in Health and Disease," uses targeted high-dimensional flow cytometry, unsupervised clustering, and in vivo tracing to characterize receptor signatures of intestine-adapted eosinophils across healthy and inflammatory states. The research identifies conserved features that foreshadow T cell modulatory functions and explores how intestine-adapted eosinophils contribute to immune homeostasis versus pathologic infiltration in food allergies, eosinophilic gastrointestinal disorders, eosinophilic granulomatosis with polyangiitis, and inflammatory bowel disease. The work employs novel mouse models to disrupt intestinal eosinophil adaptations and reveal distinct developmental trajectories in healthy versus inflamed tissue, including the role of inhibitory C-type lectins in autocrine regulation.

Performance occurs in Aurora, Colorado, over a five-year period from September 1, 2026, through August 31, 2031. The award is classified as a Project Grant, a standard assistance type under the NIAID program supporting biomedical research in infectious and allergic diseases at academic and nonprofit institutions.

Abstract

The gastrointestinal (GI) tract is a unique niche, balancing nutrient absorption with immune homeostasis at a host:microbial interface. GI resident eosinophils exhibit adaptations, dynamically shaped by the microenvironment, that equip their unique contributions to immune, metabolic, and tissue homeostasis. Juxtaposed with these homeostatic functions, extra-physiologic infiltration of eosinophils is considered pathologic in diseases such as food allergies, eosinophilic gastrointestinal disorders (egids), eosinophilic granulomatosis with polyangiitis (egpa), and inflammatory bowel diseases (IBD). Fundamental questions remain unanswered. How do intestinal eosinophils contribute to immune homeostasis? What distinguishes tissue eosinophils with homeostatic versus pathologic potentials? Long-term goals of this project are to understand homeostatic immune-regulatory and pathologic roles of intestinal eosinophils with the ultimate aim of developing precision eosinophil-modulating therapies. In preliminary data included here, we combined targeted high dimensional flow cytometry, unsupervised clustering, and in vivo tracing to identify conserved receptor signatures of intestine-adapted eosinophils across health and disease. Receptor signatures of intestine-adapted eosinophils conserved across health and inflammatory states foreshadow t cell modulatory functions. Using novel mouse models created in-house to disrupt intestinal eosinophil adaptations, we reveal a novel indispensable role for intestine-adapted eosinophils in development of an inducible intraepithelial lymphocyte subset generated in response to microbial- and dietary-derived antigens. We also demonstrated separate trajectories in healthy versus inflamed tissue, with healthy (but not inflamed) tissue imprinting expression of an inhibitory c-type lectin that in other cells has been shown capable of autocrine stimulation that mediates cellular functional restraint. Building on these findings, this proposal explores the unifying hypothesis that intestinal adaptations equip eosinophil immunoregulatory functions and program their homeostatic (functionally restrained) versus pathologic (unrestrained) potentials. In aim 1 we will expand the surface receptor proteome of intestinal eosinophil subsets and test the conceptually novel hypothesis that the healthy GUT imprints inhibitory c-type lectin expression on eosinophils that restrains eosinophil activation, preventing overt pathologic functions such as cytolytic degranulation. Aim 2 will determine the underlying mechanisms of eosinophil regulation of IEL subsets, and disease consequences of their dysregulation. Translational aim 3 will determine the extent to which receptor signatures of intestine- adapted eosinophil subsets are recapitulated in human tissues and modulated within the context of egids.