Single‐Cell Profiling Links T‐Cell Accumulation and T H 2 / T H 17 Dynamics to Eosinophilic Esophagitis ( EoE ) Activity in Children

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ABSTRACT Background According to current guidelines, disease activity in eosinophilic esophagitis (EoE) is measured based on eosinophil infiltration in the esophageal tissue. To investigate the functional role of non‐eosinophilic immune cells, we examined immune cell infiltrate over the disease course in pediatric patients with EoE and performed single‐cell molecular analysis of the T‐cell infiltrate. Methods We collected clinical data and biopsies from pediatric patients with EoE ( N = 50, baseline, up to six follow‐up endoscopies), gastroesophageal reflux disease (GERD, N = 33), or functional disorders (FD, N = 67). Multiparametric immunofluorescence staining (mIF; n = 114 biopsies) and single‐cell RNA sequencing of CD45 + CD3 + T‐cells ( n = 82 biopsies; 35,112 cells) with T cell receptor repertoire analysis were performed. Results Immune cell infiltration was significantly higher in active EoE than in inactive EoE, GERD, and FD (inactive: EPX p = 0.0156, MCT p = 0.0312, CD3 p = 0.0078). During remission, CD8 + T‐cell infiltration was significantly greater with PPI treatment compared to TS ( p = 0.0092). GNLY‐positive activated CD8 + T‐cells ( R = 0.33, p = 0.038), and T H 2 cells ( R = 0.36, p = 0.036) positively correlated with esophageal eosinophilia in the single‐cell analysis, whereas IL17‐positive CD4 + T‐cells showed a negative correlation ( R = −0.43, p = 0.016 ) . During active EoE, T H 2 cells were enriched ( p = 0.002). Absolute clone size was higher in active EoE than in inactive EoE and controls, while mean clone size only differed for CD4 clones between active EoE and controls. Diversity and the ratio of expanded clonotypes did not differ. Conclusion Distinct immunophenotypic profiles are associated with treatment response and disease activity in pediatric EoE. TS were associated with lower residual T cell infiltration than PPI. The evaluation of therapy‐induced phenotypic changes by single‐cell analysis was limited by low T cell yields in biopsies after TS treatment.

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