{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:13:29Z","timestamp":1792628009630,"version":"4.5.0"},"reference-count":32,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"110","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Immunol."],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>\n            Human CD4\n            <jats:sup>+<\/jats:sup>\n            T cells play a central role in the pathogenesis of autoimmune diseases, but their immunoregulatory mechanisms driving pathogenesis remain to be elucidated. We show that human T peripheral helper cells (T\n            <jats:sub>PH<\/jats:sub>\n            cells) regulate peripheral immune responses via insulin-like growth factor\u2013like family member 2 (IGFL2), an inflammatory factor found exclusively in primates. Single-cell RNA sequencing of seropositive rheumatoid arthritis (RA) synovium showed that\n            <jats:italic toggle=\"yes\">IGFL2<\/jats:italic>\n            is specifically expressed by CD4\n            <jats:sup>+<\/jats:sup>\n            T cells, predominantly T\n            <jats:sub>PH<\/jats:sub>\n            cells. IGFL2 promotes transforming growth factor\u2013\u03b2\u2013induced CXCL13 production in CD4\n            <jats:sup>+<\/jats:sup>\n            T cells, activates nuclear factor \u03baB signaling, and induces monocyte gene signatures like those of pathogenic macrophages. CRISPR-Cas9 knockout of IGFL2 in synovial T\n            <jats:sub>PH<\/jats:sub>\n            cells suppressed this gene signature in cocultured monocytes. Blood IGFL2 protein levels correlated with RA disease severity and could be used as a potential biomarker. These findings highlight the involvement of IGFL2 in RA pathogenesis, emphasizing how human T\n            <jats:sub>PH<\/jats:sub>\n            cells regulate local immune responses via IGFL2.\n          <\/jats:p>","DOI":"10.1126\/sciimmunol.adr3838","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T17:58:56Z","timestamp":1754071136000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":15,"title":["Human CD4\n            <sup>+<\/sup>\n            T cells regulate peripheral immune responses in rheumatoid arthritis via insulin-like growth factor\u2013like family member 2"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4666-5326","authenticated-orcid":true,"given":"Akinori","family":"Murakami","sequence":"first","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan."},{"name":"Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan."},{"name":"Kyoto University Immunomonitoring Center, Kyoto University, Kyoto, Japan."},{"name":"Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinko","family":"Akamine","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6817-5235","authenticated-orcid":true,"given":"Shiro","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7896-3937","authenticated-orcid":true,"given":"Koichi","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan."},{"name":"Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8327-3826","authenticated-orcid":true,"given":"Kohei","family":"Nishitani","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1827-382X","authenticated-orcid":true,"given":"Hiromu","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan."},{"name":"Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan."},{"name":"Department of Orthopaedic Surgery, Kurashiki Central Hospital, Kurashiki, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1089-5296","authenticated-orcid":true,"given":"Ryu","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6556-1226","authenticated-orcid":true,"given":"Takayuki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan."},{"name":"Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9326-3699","authenticated-orcid":true,"given":"Takeshi","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3515-173X","authenticated-orcid":true,"given":"Yuki","family":"Masuo","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3363-7793","authenticated-orcid":true,"given":"Osamu","family":"Iri","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1308-7080","authenticated-orcid":true,"given":"Shinichiro","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2526-2974","authenticated-orcid":true,"given":"Shinichi","family":"Kuriyama","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7674-1815","authenticated-orcid":true,"given":"Yugo","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 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