Clonally expanded, GPR15-expressing pathogenic effector T_H2 cells are associated with eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the recruitment of eosinophils to the esophagus, resulting in chronic inflammation. We sought to understand the cellular populations present in tissue biopsies of patients with EoE and to determine how these populations are altered between active disease and remission. To this end, we analyzed cells obtained from esophageal biopsies, duodenal biopsies, and peripheral blood of patients with EoE diagnosed with active disease or remission with single-cell RNA and T cell receptor (TCR) sequencing. Pathogenic effector T_H2 (peT_H2) cells present in the esophageal biopsies of patients with active disease expressed distinct gene signatures associated with the synthesis of eicosanoids. The esophageal tissue-resident peT_H2 population also exhibited clonal expansion, suggesting antigen-specific activation. Peripheral CRTH2⁺CD161^- and CRTH2⁺CD161⁺ memory CD4⁺ T cells were enriched for either a conventional T_H2 phenotype or a peT_H2 phenotype, respectively. These cells also exhibited substantial clonal expansion and convergence of TCR sequences, suggesting that they are expanded in response to a defined set of antigens. The esophagus-homing receptor GPR15 was up-regulated by peripheral peT_H2 clonotypes that were also detected in the esophagus. Finally, GPR15⁺ peT_H2 cells were enriched among milk-reactive CD4⁺ T cells in patients with milk-triggered disease, suggesting that these cells are an expanded, food antigen-specific population with enhanced esophagus homing potential.