Dysregulated IL-2 signaling and T-cell subset shifts are associated with eosinophilic esophagitis activity

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disorder of the esophagus. However, the T-cell transcriptional programs distinguishing active disease from remission remain incompletely understood. In this study, we applied single-cell RNA sequencing to esophageal biopsies obtained from normal subjects and patients in remission or with active EoE, to characterize T-cell heterogeneity, state-dependent transcriptional changes, and intercellular communication networks. After stringent quality control, no substantial batch effects were observed. We identified five major T-cell subsets, with natural killer T (NKT) cells representing the most abundant population. Notably, naïve T cells and T helper 2 (Th2) cells were detected exclusively in active EoE samples, whereas regulatory T (Treg) and Th17 cells were present in all groups. The abundance of Tregs surpassed that of Th17 cells in active EoE but was similar to Th17 levels in normal and remission tissues. Functional enrichment analysis revealed a preferential association of NKT cells with receptor-binding functions. Th2 and naïve T cells shared signatures related to ribosome biology; naïve T cells additionally exhibited 5′-UTR binding and translation-regulator activity, aligning with their maturation potential. Consistent with the non-malignant nature of EoE, copy-number variation signals were minimal. Cell-type-specific differential expression analysis uncovered activated immune programs in NKT cells from active EoE, enriched for cytokine activity, along with epigenetic and transcriptional alterations in Tregs, including demethylase-linked functions, and protein-folding-related changes in Th17 cells. Cell-cell communication inference indicated a substantial rewiring of interaction networks in active EoE, suggesting activation of IL-16, IL-10, TRAIL, and PECAM1 pathways and heightened outgoing signaling from Th2 cells. Across all conditions, NKT cells served as dominant signaling senders and receivers. Collectively, these results delineate the T-cell composition and signaling circuits specific to active EoE, offering mechanistic insights into the maintenance of disease activity.