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

Sci Immunol. 2023 Jan 6;8(79):eabp9940. doi: 10.1126/sciimmunol.abp9940. Epub 2023 Jan 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Enteritis
  • Eosinophilia
  • Eosinophilic Esophagitis* / genetics
  • Gastritis
  • Hypersensitivity, Immediate*
  • Inflammation
  • Mice
  • Receptors, Transforming Growth Factor beta / genetics

Substances

  • Receptors, Transforming Growth Factor beta

Supplementary concepts

  • Eosinophilic enteropathy