{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:12:10Z","timestamp":1792087930860,"version":"4.4.0"},"reference-count":31,"publisher":"American Society for Clinical Investigation","issue":"21","license":[{"start":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T00:00:00Z","timestamp":1699401600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Allergy and Immunology Institute, NHLBI","award":["R01AI156274,R01AI07761,T32HL007227,R35HL135827,P41EB028239-01,F31-HL143905"],"award-info":[{"award-number":["R01AI156274,R01AI07761,T32HL007227,R35HL135827,P41EB028239-01,F31-HL143905"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["23POST1026402"],"award-info":[{"award-number":["23POST1026402"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R35-HL166565-01"],"award-info":[{"award-number":["R35-HL166565-01"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,8]]},"abstract":"<jats:p>\n                    MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however, sustained mTORC1 activation prevents generation of long-lived memory CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Here we show that manipulating TSC2 at Ser1365 potently regulated activated but not basal mTORC1 signaling in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Unlike nonstimulated TSC2-KO cells, CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells expressing a phosphosilencing mutant TSC2-S1365A (TSC2-SA) retained normal basal mTORC1 activity. PKC and T cell receptor (TCR) stimulation induced TSC2 S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and T cell effector function. Consequently, SA CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells displayed greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells also displayed enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, SA CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells used as adoptive cell therapy displayed greater antitumor immunity than WT CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhanced both T cell effector function and long-term persistence\/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.167829","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T09:28:56Z","timestamp":1696411736000},"source":"Crossref","is-referenced-by-count":15,"title":["TSC2 S1365A mutation potently regulates CD8+ T cell function and differentiation and improves adoptive cellular cancer therapy"],"prefix":"10.1172","volume":"8","author":[{"given":"Chirag H.","family":"Patel","sequence":"first","affiliation":[{"name":"Bloomberg-Kimmel Institute for Immunotherapy,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9802-4953","authenticated-orcid":true,"given":"Yi","family":"Dong","sequence":"additional","affiliation":[{"name":"Bloomberg-Kimmel Institute for Immunotherapy,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3021-3894","authenticated-orcid":true,"given":"Navid","family":"Koleini","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8364-9467","authenticated-orcid":true,"given":"Xiaoxu","family":"Wang","sequence":"additional","affiliation":[{"name":"Bloomberg-Kimmel Institute for Immunotherapy,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4684-5861","authenticated-orcid":true,"given":"Brittany L.","family":"Dunkerly-Eyring","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Wen","sequence":"additional","affiliation":[{"name":"Bloomberg-Kimmel Institute for Immunotherapy,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4970-8988","authenticated-orcid":true,"given":"Mark J.","family":"Ranek","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, and"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Bartle","sequence":"additional","affiliation":[{"name":"CRISPR Therapeutics, South Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel B.","family":"Henderson","sequence":"additional","affiliation":[{"name":"CRISPR Therapeutics, South Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Sagert","sequence":"additional","affiliation":[{"name":"CRISPR Therapeutics, South Boston, Massachusetts, 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