EPITHELIAL CELL-INTRINSIC REGULATION OF FOOD ANTIGEN-DEPENDENT EOSINOPHILIC ESOPHAGITIS

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Immunology
Discipline
Immunology and Infectious Disease
Biology
Biology
Subject
Eosinophilic Esophagitis
Esophageal epithelial cells
food allergy
Interferon gamma
Major Histocompatibility Complex II
Regulatory T cells
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Copyright date
2024
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Author
Rodríguez-López, Eric, Miguel
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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
Hill, David, A.
Eisenlohr, Laurence, C.
Date of degree
2024
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