{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:05:19Z","timestamp":1789758319685,"version":"4.0.1"},"reference-count":71,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beijing Municipal Science and Technology Commission","award":["Z171100002217064"],"award-info":[{"award-number":["Z171100002217064"]}],"id":[{"id":"https:\/\/ror.org\/034k14f91","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    B7-H4, a member of the B7 family, is broadly expressed on various cancer cells and has been implicated in negative immune regulation, particularly in suppressing anti-tumor immunity. However, its receptor and the mechanisms underlying its immunosuppression remain poorly understood. Here, we identify Galectin-9 (Gal-9) as a binding partner of B7-H4 and investigate its role in modulating T cell responses. We show that glycosylation within the IgC domain of B7-H4 is required for Gal-9 binding, while the N-terminal carbohydrate recognition domain (N-CRD) of Gal-9\u2014specifically residue R65\u2014is essential for its binding with B7-H4. In addition, several other B7 family members (B7.1, B7.2, B7-H2, and B7-DC) and immune cell surface receptors (CD28, 2B4, CD226, and SLAMF1) also bind to Gal-9 at levels comparable to those observed with B7-H4 or TIM-3.\n                    <jats:italic>In vitro<\/jats:italic>\n                    functional assays revealed that B7-H4 inhibits Gal-9-induced activation of CD28 downstream signaling and reduces Gal-9-mediated T cell death.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , Gal-9 deficiency in mice resulted in an increased proportion of splenic CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, whereas B7-H4 deficiency produced no detectable phenotype. Moreover, B7-H4 and Gal-9 double-knockout mice showed no additive phenotype compared with Gal-9 single-knockout mice, and tumor growth following tumor cell challenge was unaffected in all three knockout models. Collectively, these findings indicate that B7-H4, Gal-9, other B7 family members, and T cell surface immune receptors form a complex regulatory network that modulates T cell activity and anti-tumor responses, with no single component exerting a dominant effect. This study provides a detailed molecular characterization of the B7-H4\u2013Gal-9 interaction and uncovers additional Gal-9 binding partners, offering insights into the finely tuned immune regulation mediated by the B7 family.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0355964","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:02:07Z","timestamp":1789754527000},"page":"e0355964","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Galectin-9 (Gal-9) as a B7-H4 binding partner and characterization of their glycosylation-dependent interaction that modulates T cell signaling within a multi-ligand\/receptor network"],"prefix":"10.1371","volume":"21","author":[{"given":"Ravear Zhiqiang","family":"Wang","sequence":"first","affiliation":[{"name":"School of Life Sciences, Beijing Normal University","place":["Beijing, China"]},{"name":"National Institute of Biological Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yang","sequence":"additional","affiliation":[{"name":"National Institute of Biological Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1272-9662","authenticated-orcid":true,"given":"Jianhua","family":"Sui","sequence":"additional","affiliation":[{"name":"National Institute of Biological Sciences","place":["Beijing, China"]},{"name":"Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"issue":"18","key":"pone.0355964.ref001","doi-asserted-by":"crossref","first-page":"10388","DOI":"10.1073\/pnas.1434299100","article-title":"B7x: a widely expressed B7 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