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Through genetic fine mapping, we identified the single\u2010nucleotide polymorphism rs80262450 in the PTPN2 gene as the putative causal variant. Analysis of GTEx tissue samples and genetically engineered myeloid cell lines carrying risk and nonrisk alleles of rs80262450 demonstrated increased expression of the PTPN2 splice isoform 4 (PTPN2.4), suggesting that the rs80262450 enhances disease susceptibility by favoring production of PTPN2.4. Furthermore, we found that PTPN2.4 contains a nuclear export sequence (NES) that leads to its retention in the cytoplasm. Differential localization of PTPN2.4 isoform results in a distinct protein binding profile revealed by mass\u2010spectrometry analysis, and its overexpression increased TNF\u2010\u03b1. PTPN2.4 knockdown reduced pro\u2010inflammatory cytokines in human macrophages. Mutations within the NES motif abolished the unique localization and function of PTPN2.4. Lastly, increased expression of PTPN2.4 was found in Crohn's disease tissues, demonstrating its involvement in the disease. Together, we identified the pathogenic isoform PTPN2.4 as a novel driver of intestinal inflammation and a potential target to attenuate inflammation in IBD.<\/jats:p>","DOI":"10.1002\/eji.70207","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:35:57Z","timestamp":1779194157000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel PTPN2 Isoform Differentially Regulates Immune Response"],"prefix":"10.1002","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0926-6561","authenticated-orcid":false,"given":"Xiaoguang","family":"Li","sequence":"first","affiliation":[{"name":"Immunology Discovery Research AbbVie, Inc.  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