Treatment-dependent T-cell infiltrate in pediatric eosinophilic esophagitis (EoE)

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\received DD MMMM YYYY \acceptedDD MMMM YYYY Background: Treatment options for Eosinophilic Esophagitis (EoE) include proton-pump-inhibitors (PPI), elimination diets (ED), and topical steroids (TS). We investigated whether differences in treatment response among children with EoE are associated with variations in immune cell composition during the disease. 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), bulk transcriptomics (n=96 biopsies), and single RNA sequencing of CD45 + CD3 + T-cells (n=81 biopsies; 36,603 cells) were performed. Results: In EoE patients, ED (±PPI) or PPI monotherapy achieved lower remission rates (41%, 28%) compared to TS (±PPI±ED; 72%), and more frequent relapses (Log-rank: p=0.002 ). Immune cell infiltration was significantly higher in active EoE than in inactive EoE, GERD, and FD (inactive: EPX p=<0.0001 , MCT p=0.0006 , CD3 p=0.0009 ). During remission, CD3 + T-cell infiltration was significantly greater with PPI treatment compared to TS ( p<0.0001 ). GNLY-producing activated CD8 + T-cells (r=0.36, p=0.026 ), and T H 2 cells (r=0.37, p=0.021 ) positively correlated with esophageal eosinophilia, whereas IL17-producing CD4 + T-cells showed a negative correlation (r=-0.43, p=0.006). No treatment-related transcriptional differences were detected. Compared to inactive disease, active EoE showed a higher mean clone size of CD8 + T-cell clonotypes (1.476 vs. 1.376, p=0.0004 ) and a greater proportion of expanded CD8 + clonotypes ( p=0.019 ). Conclusions: Distinct immunophenotypic profiles are associated with treatment response and disease activity in pediatric EoE. TS confer superior remission rates with complete resolution of cellular inflammatory response.

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