Oesophageal Epithelial Cell-Intrinsic MHCII Regulates Food Antigen-Dependent Eosinophilic Esophagitis in an IFNγ-Dependent Manner.

Abstract

BACKGROUND: Eosinophilic oesophagitis (EoE) is a chronic food allergy that causes oesophageal inflammation and dysfunction. Recent work demonstrates IFNγ-dependent gene signatures in inflamed EoE biopsies. IFNγ has been implicated in the promotion of MHCII expression on oesophageal epithelial cells (EECs). However, the regulation of EEC-MHCII expression in vivo, and its contribution to EoE, is unknown. OBJECTIVE: The objective of this study was to determine the regulation and role of EEC-intrinsic MHCII expression in EoE. METHODS: We examined the expression of HLA II-pathway transcripts in human EECs using single cell RNA-seq datasets and primary human tissues and mouse systems to interrogate the contribution of IFNγ to EEC-MHCII expression. Finally, we used a mouse disease model to test the contribution of epithelial MHCII to food antigen-dependent EoE. RESULTS: HLA II transcripts were upregulated in EECs of active EoE patients, compared with controls. Similarly, EEC-MHCII expression was higher in mice with EoE-like inflammation. EEC-MHCII expression was governed by IFNγ-responsive transcriptional regulation. EEC-specific MHCII deficiency resulted in exacerbated eosinophilic inflammation in a model of food antigen-dependent EoE. CONCLUSION: We find a novel immunoregulatory role for IFNγ-dependent EEC-MHCII in the context of oesophageal food allergy. CLINICAL RELEVANCE: Our results expand our understanding of oesophageal immune physiology and identify EEC-MHCII as mediating an anti-inflammatory axis that could be leveraged therapeutically.