{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:20:26Z","timestamp":1790835626712,"version":"4.1.0"},"reference-count":0,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,11,24]],"date-time":"2015-11-24T00:00:00Z","timestamp":1448323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:p>In the ectopic lymphoid\u2010like structures present in chronic inflammatory conditions such as rheumatoid arthritis, a subset of human effector memory CD4<jats:sup>+<\/jats:sup> T\u00a0cells that lacks features of follicular helper T (Tfh) cells produces CXCL13. Here, we report that TGF\u2010\u03b2 induces the differentiation of human CXCL13\u2010producing CD4<jats:sup>+<\/jats:sup> T\u00a0cells from na\u00efve CD4<jats:sup>+<\/jats:sup> T\u00a0cells. The TGF\u2010\u03b2\u2010induced CXCL13\u2010producing CD4<jats:sup>+<\/jats:sup> T\u00a0cells do not express CXCR5, B\u2010cell lymphoma 6 (BCL6), and other Tfh\u2010cell markers. Furthermore, expression levels of CD25 (IL\u20102R\u03b1) in CXCL13\u2010producing CD4<jats:sup>+<\/jats:sup> T\u00a0cells are significantly lower than those in FoxP3<jats:sup>+<\/jats:sup> in vitro induced Treg cells. Consistent with this, neutralization of IL\u20102 and knockdown of STAT5 clearly upregulate CXCL13 production by CD4<jats:sup>+<\/jats:sup> T\u00a0cells, while downregulating the expression of FoxP3. Furthermore, overexpression of FoxP3 in na\u00efve CD4<jats:sup>+<\/jats:sup> T\u00a0cells downregulates CXCL13 production, and knockdown of FoxP3 fails to inhibit the differentiation of CXCL13\u2010producing CD4<jats:sup>+<\/jats:sup> T\u00a0cells. As reported in rheumatoid arthritis, proinflammatory cytokines enhance secondary CXCL13 production from reactivated CXCL13\u2010producing CD4<jats:sup>+<\/jats:sup> T\u00a0cells. Our findings demonstrate that CXCL13\u2010producing CD4<jats:sup>+<\/jats:sup> T\u00a0cells lacking Tfh\u2010cell features differentiate via TGF\u2010\u03b2 signaling but not via FoxP3, and exert their function in IL\u20102\u2010limited but TGF\u2010\u03b2\u2010rich and proinflammatory cytokine\u2010rich inflammatory conditions.<\/jats:p>","DOI":"10.1002\/eji.201546043","type":"journal-article","created":{"date-parts":[[2015,11,6]],"date-time":"2015-11-06T09:44:48Z","timestamp":1446803088000},"page":"360-371","source":"Crossref","is-referenced-by-count":95,"title":["TGF\u2010\u03b2 induces the differentiation of human CXCL13\u2010producing CD4<sup>+<\/sup> T\u00a0cells"],"prefix":"10.1002","volume":"46","author":[{"given":"Shio","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"The Tazuke\u2010Kofukai Medical Research Institute, Kitano Hospital  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritoshi","family":"Furu","sequence":"additional","affiliation":[{"name":"Department of the Control for Rheumatic Diseases Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromu","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juichi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yoshitomi","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics Kyoto University Graduate School of Medicine  Kyoto Japan"},{"name":"Department of Orthopaedic Surgery Kyoto University Graduate School of Medicine  Kyoto Japan"},{"name":"Department of Tissue Regeneration Institute for Frontier Medical Sciences Kyoto University  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,11,24]]},"container-title":["European Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Feji.201546043","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Feji.201546043","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/eji.201546043","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T14:53:19Z","timestamp":1696603999000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/eji.201546043"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,24]]},"references-count":0,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016,2]]}},"alternative-id":["10.1002\/eji.201546043"],"URL":"https:\/\/doi.org\/10.1002\/eji.201546043","archive":["Portico"],"relation":{},"ISSN":["0014-2980","1521-4141"],"issn-type":[{"value":"0014-2980","type":"print"},{"value":"1521-4141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,24]]}}}