{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T05:54:13Z","timestamp":1781243653544,"version":"3.54.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DP3-DK111802"],"award-info":[{"award-number":["DP3-DK111802"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009992","name":"Seattle Children\u2019s Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009992","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018762","name":"Seattle Children\u2019s Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018762","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018762","name":"Benaroya Family Gift Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018762","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>FOXP3+ regulatory T cells (Treg) are required for maintaining immune tolerance and preventing systemic autoimmunity. PI3K\u03b4 is required for normal Treg development and function. However, the impacts of dysregulated PI3K\u03b4 signaling on Treg function remain incompletely understood. In this study, we used a conditional mouse model of activated PI3K\u03b4 syndrome to investigate the role of altered PI3K\u03b4 signaling specifically within the Treg compartment. Activated mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) specifically within the Treg compartment exhibited weight loss and evidence for chronic inflammation, as demonstrated by increased memory\/effector CD4+ and CD8+ T cells with enhanced IFN-\u03b3 secretion, spontaneous germinal center responses, and production of broad-spectrum autoantibodies. Intriguingly, aPIK3CD facilitated Treg precursor development within the thymus and an increase in peripheral Treg numbers. Peripheral Treg, however, exhibited an altered phenotype, including increased PD-1 expression and reduced competitive fitness. Consistent with these findings, Treg-specific aPIK3CD mice mounted an elevated humoral response following immunization with a T cell\u2013dependent Ag, which correlated with a decrease in follicular Treg. Taken together, these findings demonstrate that an optimal threshold of PI3K\u03b4 activity is critical for Treg homeostasis and function, suggesting that PI3K\u03b4 signaling in Treg might be therapeutically targeted to either augment or inhibit immune responses.<\/jats:p>","DOI":"10.4049\/jimmunol.2400032","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T12:55:22Z","timestamp":1717419322000},"page":"135-147","source":"Crossref","is-referenced-by-count":6,"title":["Activated PI3K\u03b4 Specifically Perturbs Mouse Regulatory T Cell Homeostasis and Function Leading to Immune Dysregulation"],"prefix":"10.1093","volume":"213","author":[{"given":"Akhilesh K","family":"Singh","sequence":"first","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5022-9917","authenticated-orcid":false,"given":"Fahd","family":"Al Qureshah","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"},{"name":"Department of Immunology, University of Washington , Seattle, WA"},{"name":"Wellness and Preventive Medicine Institute, King Abdulaziz City for Science and Technology , Riyadh ,","place":["Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1302-3872","authenticated-orcid":false,"given":"Travis","family":"Drow","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0892-0181","authenticated-orcid":false,"given":"Baidong","family":"Hou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0810-1776","authenticated-orcid":false,"given":"David J","family":"Rawlings","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"},{"name":"Department of Immunology, University of Washington , Seattle, WA"},{"name":"Department of Pediatrics, University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"key":"2025012305112083400_r1","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1126\/science.1079490","article-title":"Control of regulatory T cell development by the transcription factor Foxp3","volume":"299","author":"Hori","year":"2003","journal-title":"Science"},{"key":"2025012305112083400_r2","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ni904","article-title":"Foxp3 programs the development and function of CD4+CD25+ regulatory T cells","volume":"4","author":"Fontenot","year":"2003","journal-title":"Nat. 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