{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:08:48Z","timestamp":1785557328586,"version":"3.56.0"},"reference-count":44,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2019YFE0111700"],"award-info":[{"award-number":["2019YFE0111700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The goal was to investigate the role and intracellular regulatory mechanisms of double\u2010negative T (DNT) cells in the pathogenesis of systemic lupus erythematosus (SLE).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>DNT cells were assessed in murine models, patients with SLE, and controls using flow cytometry (FCM). DNT cells from either resiquimod (R848) or vehicle\u2010treated C57BL\/6 (B6) mice were cultured with B cells from R848\u2010treated mice to explore functions. Differential mechanistic target of rapamycin (mTOR) pathway signaling in DNT cells measured using FCM and quantitative polymerase chain reaction was validated by rapamycin inhibition. Candidate lipid metabolites detected using liquid chromatography with electrospray ionization mass spectrometry\/mass spectrometry were functionally assessed in DNT cell cultures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DNT cells were markedly increased in both spontaneous and induced mouse lupus models and in patients with SLE. Expanded DNT cells from R848\u2010treated B6 mice produced elevated interleukin (IL)\u201017A and IgG with increased germinal center B (GCB) cells. Expansion of DNT cells associated with activation of mTORC1 pathway that both IL\u201017A levels and the number of DNT cells exhibited dose\u2010dependent reduction with rapamycin treatment. Lipidomics studies revealed differential patterns of lipid metabolites in T cells of R848\u2010treated mice. Among candidate metabolites, elevated phosphatidic acid (PA) that was partially controlled by phospholipase D2 increased the expression of the mTORC1 downstream target p\u2010S6 and positively expanded IL\u201017A\u2013producing DNT cells. Similarly, elevated proportions of circulating DNT cells in patients with SLE correlated with disease activity and proteinuria, and IL\u201017A secretion was elevated after in vitro PA stimulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The accumulation of PA in T cells could activate the mTORC1 pathway, promoting DNT cell expansion and IL\u201017A secretion, resulting in GCB cell abnormalities in lupus.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42840-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42840","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T03:59:02Z","timestamp":1709524742000},"page":"1096-1108","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Phosphatidic Acid Promoting the Generation of <scp>Interleukin\u201017A<\/scp> Producing <scp>Double\u2010Negative<\/scp> T Cells by Enhancing <scp>mTORC1<\/scp> Signaling in Lupus"],"prefix":"10.1002","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2231-1371","authenticated-orcid":false,"given":"Wenjing","family":"Li","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School  Nanjing 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