{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:13:07Z","timestamp":1781107987713,"version":"3.54.1"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"42","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFA0912400"],"award-info":[{"award-number":["2022YFA0912400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National natural science foundation of China","doi-asserted-by":"crossref","award":["82230055"],"award-info":[{"award-number":["82230055"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,10,21]]},"abstract":"<jats:p>\n                    The T cell receptor (TCR), a master regulator of adaptive immunity, serves as a molecular transducer that converts antigen recognition into precisely modulated intracellular signals, orchestrating both T cell development and effector functions. In this study, we leveraged a germline CD3\u03b5\n                    <jats:sup>I173A<\/jats:sup>\n                    mutation, a previously characterized alteration that amplifies TCR signaling through the disruption of inhibitory lipid interactions, to dissect how thymocyte-intrinsic TCR signaling amplification influences the fate of mature T cells. Remarkably, thymic double-positive cells in CD3\u03b5\n                    <jats:sup>I173A<\/jats:sup>\n                    mice with altered TCR repertoires demonstrated a significant downregulation of the phosphatidylserine decarboxylase homolog gene\n                    <jats:italic toggle=\"yes\">AC149090.1<\/jats:italic>\n                    . This modulation triggered a comprehensive rewiring of lipid metabolic pathways, establishing a systemic compensatory mechanism to counterbalance excessive TCR signaling. These metabolic adaptations culminated in functionally compromised mature T cells, characterized by diminished activation potential, reduced proliferative capacity, and impaired antitumor efficacy in CD3\u03b5\n                    <jats:sup>I173A<\/jats:sup>\n                    mice. Our results underscore the critical role of thymic TCR signaling in T cell development for sustaining immune homeostasis and orchestrating mature T cell functionality, unveiling the lipid metabolic plasticity during thymocyte development that acts as a critical regulatory checkpoint for maintaining immune homeostasis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2507154122","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T18:14:11Z","timestamp":1760638451000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["TCR signal\u2013enhancing mutation alters lipid metabolism of thymocytes and impairs antitumor immunity of mature T cells"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8159-7720","authenticated-orcid":false,"given":"Wenhua","family":"Liang","sequence":"first","affiliation":[{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children\u2019s Hospital, Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuge","family":"Liang","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children\u2019s Hospital, Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhu","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children\u2019s Hospital, Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenshuang","family":"Ji","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children\u2019s Hospital, Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"State Key Laboratory of Oncogenes and 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Liang Single-cell sequencing data supporting the publication \u201cTCR signal\u2013enhancing mutation alters lipid metabolism of thymocytes and impairs antitumor immunity of mature T cells.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE288784. Deposited 5 February 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2507154122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T18:14:46Z","timestamp":1760638486000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2507154122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":33,"journal-issue":{"issue":"42","published-print":{"date-parts":[[2025,10,21]]}},"alternative-id":["10.1073\/pnas.2507154122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2507154122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,16]]},"assertion":[{"value":"2025-04-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2507154122"}}