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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,12,5]]},"abstract":"<jats:p>\n                    Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of\n                    <jats:italic>Usp7<\/jats:italic>\n                    or\n                    <jats:italic>Gzma<\/jats:italic>\n                    and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1\n                    <jats:sup>+<\/jats:sup>\n                    and granzyme\n                    <jats:sup>+<\/jats:sup>\n                    Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2302903120","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T13:35:15Z","timestamp":1701178515000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":25,"title":["The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9305-0423","authenticated-orcid":false,"given":"Jin","family":"Kumagai","sequence":"first","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"},{"name":"Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba 260-8670, 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