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Epithelial-intrinsic defects in TGFβR signaling drive local allergic inflammation manifesting as eosinophilic esophagitis

K. Laky,Jessica Kinard,J. Li,Ian N. Moore,J. Lack,E. Fischer,J. Kabat,R. Latanich,N. Zachos,Ajinkya R. Limkar,Katherine A. Weissler,Robert W. Thompson,T. Wynn,H. Dietz,A. Guerrerio,P. Frischmeyer-Guerrerio

Published 2023 in Science immunology

ABSTRACT

Allergic diseases are a global health challenge. Individuals harboring loss-of-function variants in transforming growth factor–β receptor (TGFβR) genes have an increased prevalence of allergic disorders, including eosinophilic esophagitis. Allergic diseases typically localize to mucosal barriers, implicating epithelial dysfunction as a cardinal feature of allergic disease. Here, we describe an essential role for TGFβ in the control of tissue-specific immune homeostasis that provides mechanistic insight into these clinical associations. Mice expressing a TGFβR1 loss-of-function variant identified in atopic patients spontaneously develop disease that clinically, immunologically, histologically, and transcriptionally recapitulates eosinophilic esophagitis. In vivo and in vitro, TGFβR1 variant–expressing epithelial cells are hyperproliferative, fail to differentiate properly, and overexpress innate proinflammatory mediators, which persist in the absence of lymphocytes or external allergens. Together, our results support the concept that TGFβ plays a fundamental, nonredundant, epithelial cell–intrinsic role in controlling tissue-specific allergic inflammation that is independent of its role in adaptive immunity. Description TGFβ is an essential nonredundant epithelial cell-intrinsic controller of allergic inflammation independent of its role in adaptive immunity. Eosinophilic esophagitis essentials Individuals with loss-of-function variants of transforming growth factor–β receptor (TGFβR) genes develop allergic diseases including eosinophilic esophagitis (EoE), but mechanisms driving disease pathology are not well understood. Here Laky et al. define an essential role for TGFβR in maintaining epithelial cell homeostasis to control allergic inflammation. Mice bearing TGFβR1 loss-of-function variants developed disease symptoms consistent with EoE, which was reflected in pathological, immunological, and transcriptional changes to esophagus. Expression of TGFβR1 variants in epithelial cells was associated with hyperproliferation, defects in differentiation, and the release of pro-inflammatory mediators, even in the absence of allergens or lymphocytes. These findings highlight an epithelial cell–intrinsic function of TGFβR1 in modulating allergic inflammation associated with EoE. —CNF

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