{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T15:10:40Z","timestamp":1788793840317,"version":"build-2803163510"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"6","funder":[{"name":"Intramural Research Program of the National Institutes of Health"},{"DOI":"10.13039\/100000072","name":"the National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Young Scientists Fund of the National Natural Science Foundation of China","award":["32300742"],"award-info":[{"award-number":["32300742"]}]},{"name":"the Songjiang District Medical Technology Breakthrough Program","award":["2024SJKJGG073"],"award-info":[{"award-number":["2024SJKJGG073"]}]},{"DOI":"10.13039\/501100012600","name":"ShanghaiTech University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012600","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes of Health, National Institute of Dental and Craniofacial Research"},{"name":"Peking Union Medical College, and currently works in Shanghai General Hospital"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gamma delta (\u03b3\u03b4) T cells undergo a distinct developmental pathway within the thymus, where transforming growth factor \u03b2 (TGF-\u03b2) exerts pivotal regulatory influence. However, the precise mechanistic contributions of TGF-\u03b2 to \u03b3\u03b4 T cells differentiation and functional maturation remain incompletely understood. Here, we show that TGF-\u03b2 regulates the activation state, migration capacity and inflammatory cytokine production during the development of \u03b3\u03b4 T cells in the thymus. Specifically, \u03b3\u03b4 T cells deficient in TGF-\u03b2 signaling (Tgfbr1 deficient or Smad2 and Smad3 double deficient) predominantly acquired a CD44+CD45RB+ phenotype and showed impaired thymic egress, with reduced expression of CCR9, CD24, and Cxcr4. These knockout \u03b3\u03b4 T cells also exhibited elevated production of proinflammatory cytokines (interferon \u03b3, interleukin-17A, tumor necrosis factor \u03b1) specifically in the thymus. RNA sequencing revealed that Tgfbr1-deficient \u03b3\u03b4 T cells upregulated genes associated with T cell receptor signaling, cytotoxicity, and immune activation while downregulating migration-related genes. T cell receptor repertoire sequencing further demonstrated that thymic \u03b3\u03b4 T cells lacking TGF-\u03b2 signaling exhibited reduced clonal diversity accompanied by expansion of dominant clonotypes, indicating a role for TGF-\u03b2 in maintaining repertoire breadth during \u03b3\u03b4 T cell development. However, we found that the differentiation of V\u03b31+, V\u03b34+, and V\u03b37+ subsets in the thymus of the TGF-\u03b2 signal\u2013deficient mice remained largely intact. Our findings advance mechanistic understanding of \u03b3\u03b4 T cell ontogeny and underscore the role of TGF-\u03b2 in balancing effector function with thymic retention or peripheral dissemination.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag134","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:05:13Z","timestamp":1783011913000},"source":"Crossref","is-referenced-by-count":0,"title":["TGF-\u03b2 controls developmental fate and functional identity of thymic \u03b3\u03b4 T cells"],"prefix":"10.1093","volume":"215","author":[{"given":"Jiajia","family":"Han","sequence":"first","affiliation":[{"name":"Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health , Bethesda, MD,","place":["United States"]},{"name":"Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dunfang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health , Bethesda, MD,","place":["United States"]},{"name":"Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , Chengdu,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Liu","sequence":"additional","affiliation":[{"name":"Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Jin","sequence":"additional","affiliation":[{"name":"Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, ShanghaiTech University , Shanghai,","place":["China"]},{"name":"State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University , Shanghai,","place":["China"]},{"name":"Shanghai Clinical Research and Trial Center , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"2026090710431834000_vkag134-B1","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1146\/annurev.immunol.18.1.975","article-title":"[gamma][delta] cells: a right time and a right place for a conserved third way of protection","volume":"18","author":"Hayday","year":"2000","journal-title":"Annu Rev Immunol"},{"key":"2026090710431834000_vkag134-B2","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nri3384","article-title":"Six-of-the-best: unique contributions of \u03b3\u03b4 T cells to 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