IFNγ Signaling Impairs Regulatory B Cell Function Resulting in Worse Control of Esophageal Food Allergy

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ABSTRACT Background Eosinophilic Esophagitis (EoE) is a chronic food allergy that causes esophageal inflammation and fibrosis and manifests with symptoms of reflux, chest pain, swallowing difficulty, and food impactions. Though the prevalence of EoE is increasing by ~15% each year, our understanding of EoE immunopathology is limited. A noted feature of EoE is the presence of food‐specific IgG4 antibodies in the circulation and esophageal tissue. Production of IgG4 is confined to IL‐10+ B cells (Bregs) in other allergic diseases, suggesting Bregs may be present in EoE. Methods We examined circulating Bregs in patients with EoE milk allergy. In parallel, we performed mechanistic investigations of the role of Bregs in a murine model of food‐antigen‐dependent EoE. Flow cytometry and histologic analyses were used to assess esophageal and draining lymph node immune cells, and in vitro assays were used to evaluate Breg functional capacity. Results Breg frequency was reduced in both EoE milk allergic subjects and an EoE disease model. Murine Breg suppressive capacity was impaired during EoE‐like inflammation. Inducible deletion of Breg‐derived IL‐10 worsened EoE‐like inflammation, while adoptive transfer of IL‐10 sufficient Bregs suppressed DC activation and improved esophageal eosinophilia. IFNγ was sufficient to suppress Breg expansion and IL‐10 production in vitro and contributed to Breg dysfunction and esophageal inflammation in vivo. Conclusion Bregs play an immunoregulatory role during EoE by controlling esophageal eosinophilia but are functionally impaired due to IFNγ‐mediated signaling. These findings have important implications for understanding EoE's etiology and implementing future therapies that target IFNγ.

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