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A recent clinical trial of milk epicutaneous immunotherapy (EPIT) has shown initial promise, with 47% of treated EoE patients tolerating milk without recurrence of disease. Mechanisms of EPIT in EoE have not been studied in humans. Here, we identify transcriptional changes in the peripheral CD4<jats:sup>+<\/jats:sup> T\u2010cell compartment during active EoE and following EPIT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>RNA isolation, sequencing and integrative data analysis were performed on peripheral CD4<jats:sup>+<\/jats:sup> T cells isolated from 15 of 20 patients enrolled in a clinical trial of EPIT for EoE. Gene expression changes in peripheral CD4<jats:sup>+<\/jats:sup> T cells were examined during diet therapy and following trial of milk antigen EPIT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identify 244 differentially expressed genes in peripheral blood CD4<jats:sup>+<\/jats:sup> cells of EoE patients consuming versus those eliminating milk, and 129 DEGs in CD4<jats:sup>+<\/jats:sup> cells were isolated after EPIT versus after placebo (FDR\u00a0\u2264\u00a00.05). Gene set enrichment analysis identifies enrichment of hallmark interferon\u2010\u03b1 and interferon\u2010\u03b3 response pathways in peripheral CD4<jats:sup>+<\/jats:sup> T cells from EoE patients during active disease on a milk\u2010containing diet. We demonstrate overlap of this gene signature with the altered gene expression signature seen in EoE patient biopsy tissue. EPIT therapy response is associated with significant enrichment in pathways related to T\u2010cell receptor signalling (<jats:italic>P<\/jats:italic>\u00a0=\u00a01.16\u00a0\u00d7\u00a010<jats:sup>\u221214<\/jats:sup>), antigen presentation and costimulation, and cytokine signalling (<jats:italic>P<\/jats:italic>\u00a0=\u00a01.11\u00a0\u00d7\u00a010<jats:sup>\u221216<\/jats:sup>), as well as upregulation of genes associated with regulatory T\u2010cell function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>EoE is associated with distinct global transcriptional changes in CD4<jats:sup>+<\/jats:sup> T cells, one feature of which is an IFN response signature. Clinically favorable response to EPIT is likely multifactorial but is associated with a distinct transcriptional profile in peripheral CD4<jats:sup>+<\/jats:sup> cells supporting the hypothesis that EPIT alters peripheral CD4<jats:sup>+<\/jats:sup> responses in EoE patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cti2.1314","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T11:27:54Z","timestamp":1626953274000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["RNA sequencing identifies global transcriptional changes in peripheral CD4<sup>+<\/sup> cells during active oesophagitis and following epicutaneous immunotherapy in eosinophilic oesophagitis"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2943-9944","authenticated-orcid":false,"given":"Melanie A","family":"Ruffner","sequence":"first","affiliation":[{"name":"Division of Allergy and Immunology The Children's Hospital of Philadelphia Philadelphia PA USA"},{"name":"Department of Pediatrics The Perelman School of Medicine at University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Informatics The Children's Hospital of Philadelphia Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Maurer","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology The Children's Hospital of Philadelphia Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda B","family":"Muir","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Perelman School of Medicine at University of Pennsylvania Philadelphia PA USA"},{"name":"Division of Gastroenterology, Hepatology, and Nutrition The Children's Hospital of Philadelphia Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Cianferoni","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology The Children's Hospital of Philadelphia Philadelphia PA USA"},{"name":"Department of Pediatrics The Perelman School of Medicine at University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen E","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology The Children's Hospital of Philadelphia Philadelphia PA USA"},{"name":"Department of Pediatrics The Perelman School of Medicine at University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M","family":"Spergel","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology The Children's Hospital of Philadelphia Philadelphia PA 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