EPITHELIAL CELL-INTRINSIC REGULATION OF FOOD ANTIGEN-DEPENDENT EOSINOPHILIC ESOPHAGITIS
Degree type
Graduate group
Discipline
Biology
Biology
Subject
Esophageal epithelial cells
food allergy
Interferon gamma
Major Histocompatibility Complex II
Regulatory T cells
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Abstract
Eosinophilic Esophagitis (EoE) is a chronic food allergy that causes esophageal inflammation and dysfunction. Recent work demonstrates IFNg-dependent gene signatures in inflamed EoE biopsies. IFNg has been implicated in the promotion of MHCII expression on esophageal epithelial cells (EECs). However, the regulation of EEC-MHCII expression in vivo, and its contribution to esophageal food allergy, is unknown. The goal of this thesis was to determine the regulation and function of EEC-intrinsic MHCII expression in food antigen-dependent EoE. We examined the expression of MHCII-pathway transcripts in human EECs using single cell RNA-seq datasets and characterized MHCII expression patterns in biopsies from EoE patients and epithelial cell organoids. In parallel, we used a mouse model of food antigen-dependent EoE to mechanistically interrogate EEC-MHCII functions in vivo. We used gain and loss-of-function approaches to determine the contribution of IFNg to EEC-MHCII expression in human and mouse models. Finally, we tested the effects of epithelial MHCII on EoE using ED-L2/I-Ab mice, which lack EEC-specific MHCII. MHCII is upregulated on EECs in active & remission EoE patients, and mice with EoE-like inflammation. In a manner similar to other non-hematopoietic cells, EEC-MHCII expression is governed by IFNg-responsive transcriptional regulation. Interestingly, we observed that EEC-specific MHCII deficiency results in lower regulatory T cell numbers and exacerbated eosinophilic inflammation in a model of food-antigen dependent EoE. In conclusion, we herein describe the IFNg-dependent regulation of EEC-MHCII. Importantly, we uncovered a novel immunoregulatory role for EEC-MHCII in the context of esophageal inflammation. These results expand our understanding of esophageal physiology and identify EEC-MHCII as an anti-inflammatory axis that could be leveraged to treat food allergy.
Advisor
Eisenlohr, Laurence, C.