Clonally expanded, GPR15-expressing pathogenic effector TH2 cells are associated with eosinophilic esophagitis

• Published in: Science immunology 2021-08, Vol.6 (62)
• Main Authors: Morgan, Duncan M, Ruiter, Bert, Smith, Neal P, Tu, Ang A, Monian, Brinda, Stone, Brandon E, Virk-Hundal, Navneet, Yuan, Qian, Shreffler, Wayne G, Love, J Christopher
• Format: Article
• Language: English
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.abi5586

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 EoE patients in active disease or remission with single-cell RNA and TCR sequencing. Pathogenic effector T H 2 (peT H 2) 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 H 2 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 H 2 phenotype or a peT H 2 phenotype, respectively. These cells also exhibited substantial clonal expansion and convergence of TCR sequences, suggesting that peripheral peT H 2 cells are expanded in response to a defined set of antigens. The esophagus-homing receptor GPR15 was upregulated by peripheral peT H 2 clonotypes that were also detected in the esophagus. Lastly, GPR15+ peT H 2 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. T H 2 cells in eosinophilic esophagitis exhibit clonotypic features of an antigen-specific response and enhanced esophagus-homing ability.