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How STAT-mediated Th cell differentiation is negatively regulated, however, is not fully understood. Here, we report that PDLIM4 binds to STAT3, 4, and 6 and suppresses gene activation mediated by these STATs. PDLIM4 acts as an adaptor that recruits PTP-BL, a protein tyrosine phosphatase, through its LIM (abnormal cell lineage 11-islet 1-mechanosensory abnormal 3) domain, facilitating dephosphorylation of STAT proteins. PDLIM4-deficiency in CD4+ T cells resulted in augmented tyrosine phosphorylation of these STAT proteins and consequently enhanced Th1, Th2, and Th17 cell differentiation, suggesting that PDLIM4 regulates the differentiation of multiple lineages of Th cells by suppressing STAT signaling. We further found that a non-synonymous single-nucleotide polymorphism in PDLIM4, which causes the substitution of a glycine residue with a cysteine in the LIM domain, is associated with susceptibility to rheumatoid arthritis and Graves\u2019 disease, both of which are known to be Th17 cell-driven autoimmune diseases. Notably, PDLIM4 containing this amino acid substitution in the LIM domain showed reduced binding to PTP-BL and was therefore partially impaired in its ability to dephosphorylate STAT3 and suppress STAT3 signaling. Our findings define an essential role of PDLIM4 in negatively regulating STAT-mediated Th-cell differentiation and preventing the onset of human autoimmune diseases.<\/jats:p>","DOI":"10.1093\/intimm\/dxag019","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T11:45:03Z","timestamp":1776944703000},"page":"555-568","source":"Crossref","is-referenced-by-count":0,"title":["PDLIM4 promotes dephosphorylation of STAT transcription factors by recruiting PTP-BL and inhibits Th1, Th2, and Th17 cell differentiation"],"prefix":"10.1093","volume":"38","author":[{"given":"Aya","family":"Jodo","sequence":"first","affiliation":[{"name":"Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakiyo","family":"Nakahira","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Hyogo Medical University , Nishinomiya, Hyogo 663-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Kochi","sequence":"additional","affiliation":[{"name":"Department of Genomic Function and Diversity, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo , Tokyo 113-8510 ,","place":["Japan"]},{"name":"Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Sugimoto-Ishige","sequence":"additional","affiliation":[{"name":"Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuneyasu","family":"Kaisho","sequence":"additional","affiliation":[{"name":"Industry-Government-Academia Collaboration Promotion 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