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Eosinophilic esophagitis (EoE) is a food allergy-associated disease characterized by esophageal eosinophilia and associated inflammation. EoE has become increasingly common in industrialized countries. However, current management strategies, such as treatment with swallowed steroids and dietary restrictions, are nonspecific or negatively impact the quality of life of EoE patients. In addition, use of more specific therapies that target immunoglobulin E (IgE) and interleukin (IL)-5 have been largely unsuccessful in ameliorating EoE. Thus, there is an urgent need to identify novel, specific immunological pathways that underlie the pathogenesis of EoE that could be targeted to treat this disease. Recently, a genome-wide association study identified that EoE is associated with a gain-of-function polymorphism in the gene that encodes thymic stromal lymphopoietin (TSLP). TSLP is an IL-7 family member cytokine that promotes allergic inflammation by eliciting T helper type 2 cytokine responses, IgE production, and the expansion of a distinct population of basophils. However, whether TSLP directly promotes allergic inflammation in the esophagus and the mechanisms by which TSLP might contribute to the pathogenesis of EoE remain unknown. Here, we describe a new murine model of experimental EoE-like disease that was used to investigate the role of TSLP in allergic inflammation of the esophagus. Murine experimental EoE-like disease developed independently of IgE but was dependent on TSLP-elicited basophils. Critically, therapeutic antibody-mediated neutralization of TSLP or depletion of basophil populations ameliorated established EoE-like disease in mice. Finally, elevated TSLP levels and exaggerated basophil responses were observed in esophageal biopsies from EoE patients, and a gain-of-function polymorphism in TSLP correlated with increased basophil responses in patients with EoE. Together, these data indicate that TSLP-elicited basophil responses may play a key role in mediating the pathogenesis of EoE, suggesting that targeting the TSLP-basophil axis could represent a new and promising therapeutic target in the treatment of EoE. [ABSTRACT FROM AUTHOR]