GPR15 and CD38 define a subset of peripheral blood pathogenic effector Th2 cells associated with active eosinophilic esophagitis

Abstract Eosinophilic esophagitis (EoE) is a chronic allergic disease driven by exposure to culprit antigens. Due to the local nature of the inflammation, diagnosis and assessment are limited to invasive procedures. Based on prior single-cell RNA sequencing (scRNA-seq) data linking peripheral GPR15+ pathogenic effector Th2 (peTh2) cells to esophageal tissue peTh2s, we hypothesized the direct involvement of GPR15+ peTh2 cells in EoE pathogenesis and aimed to further evaluate their association with EoE disease status. We subjected samples from subjects with or without EoE to flow cytometry (n = 74 peripheral blood, 17 biopsy) and scRNA-seq (n = 27 peripheral blood, 10 biopsy). Expression of GPR15 by peripheral peTh2 cells was increased in EoE, and these cells expressed increased CD38 in active EoE--findings recapitulated in esophageal biopsies. We also identified a peTh2-associated, CD38-containing gene expression program that peripheral GPR15+ peTh2 cells upregulated in active EoE. The level of upregulation was distinct from other circulating peTh2 cells and was more similar to that seen in esophageal peTh2 cells. An association between expression of GPR15 by peripheral peTh2 cells, the aryl hydrocarbon receptor was strongest in subjects with EoE, suggesting an environmental exposure or susceptibility. The magnitude of GPR15 expression by peripheral peTh2 cells could effectively in discriminate active EoE from no EoE in our study population (AUC 0.93). Our data suggest that EoE-related peTh2 cells are identifiable and accessible in the peripheral blood, and could be exploited in both clinical practice as a non-invasive biomarker and continued investigation into mechanisms driving EoE. One sentence summary GPR15 marks a subset of peripheral blood pathogenic effector Th2 cells associated with eosinophilic esophagitis (EoE) that upregulate CD38 during active disease – an observation that has potential to be used for non-invasive diagnosis and monitoring of EoE and that has suggests new mechanisms driving this increasingly prevalent allergic disease. Competing Interest Statement CMB, DMM, JCLove, and WGS are co-inventors on patent number PCT/US2025/016902 (METHODS AND MATERIALS TO DISTINGUISH BETWEEN ACTIVE EOSINOPHILIC ESOPHAGITIS (EoE), EoE IN REMISSION, AND NON-EoE STATES, publication date August 28, 2025) based on a portion of the findings in this manuscript. Additional interests as follows: CMB has received research grants from the National Institutes of Health (NIH), the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR), the Campaign Urging Research for Eosinophilic Disease (CURED), and Food Allergy Research and Education, Inc (FARE). As of December 2025, she will be employed by Sanofi, but performed the work herein, including drafting and submitting the initial manuscript while employed at MGH. JCLi is currently employed by Pfizer Inc., but performed the work herein during her fellowship training at MGH. YVV has received research grants from the NIH. NKV-H has received clinical trial funding from Regeneron and AstraZeneca. QY has received research funding and/or clinical trial funding from EvoEndo, Inc, the Food Allergy Science Initiative (FASI), the Gerber Foundation, Infinant Health. He is a medical advisor for Tiny Health. SUP has received research grants from the NIH, Food Allergy Science Initiative, and Buhlmann Laboratories. She has received clinical trial support from Regeneron and FARE. She has received consulting fees from Seismic Therapeutics and Mabylon, and royalties from Uptodate. JCLove has interests in Sunflower Therapeutics PBC, Pfizer, Honeycomb Biotechnologies, OneCyte Biotechnologies, SQZ Biotechnologies, Alloy Therapeutics, QuantumCyte, Amgen, and Repligen. His interests are reviewed and managed under the Massachusetts Institute of Technology (MIT)'s policies for potential conflicts of interest. JCLove receives sponsored research support at MIT from Amgen, the Bill & Melinda Gates Foundation, Biogen, Pfizer, Roche, Takeda, and Sanofi. WGS has received clinical trial funding from Aimmune Therapeutics, ALK, Celgene, DBV Technologies, Genentech, Novartis, Regeneron Pharmaceuticals, and Vedanta, served on scientific advisory boards for Aimmune Therapeutics and FARE, received personal consulting fees from Aimmune Therapeutics/Nestle, Harmony, Merck, and Novartis, received royalties from UpToDate, and received grants from the NIH, Demarest Lloyd Foundation, Thornhill Foundation, and FASI. DMM, JNG, EL, EGM, KC, MB, TK, AJK declare that they have no competing interests.