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.

中文翻译：

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TGFβR 信号传导中的上皮内在缺陷驱动局部过敏性炎症，表现为嗜酸性粒细胞性食管炎

过敏性疾病是全球性的健康挑战。携带转化生长因子-β受体 (TGFβR) 基因功能丧失变异体的个体患过敏性疾病的患病率增加，包括嗜酸性粒细胞性食管炎。过敏性疾病通常定位于粘膜屏障，暗示上皮功能障碍是过敏性疾病的主要特征。在这里，我们描述了 TGFβ 在控制组织特异性免疫稳态中的重要作用，该稳态提供了对这些临床关联的机制洞察。在特应性患者中发现的表达 TGFβR1 功能丧失变异体的小鼠会自发地发展出临床、免疫学、组织学和转录上与嗜酸性粒细胞性食管炎相似的疾病。在体内和体外，表达 TGFβR1 变体的上皮细胞过度增殖，无法正确区分，并过度表达先天性促炎介质，这些介质在没有淋巴细胞或外部过敏原的情况下持续存在。总之，我们的结果支持这样的概念，即 TGFβ 在控制组织特异性过敏性炎症方面起着一种基本的、非冗余的、上皮细胞内在的作用，这种作用独立于它在适应性免疫中的作用。