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Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.4\u2009years. Analysis of ligand\u2013receptor interactions revealed that type 2 cells regulate a dysfunctional subset to maintain whole-population homeostasis, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of sera after treatment revealed a higher level of circulating type 2 cytokines in 5-year or 8-year relapse-free responders. In a leukaemic mouse model, type 2\n                    <jats:sup>high<\/jats:sup>\n                    CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2\n                    <jats:sup>low<\/jats:sup>\n                    CAR T cells was attainable by enhancing their type 2 functionality, either through incorporating IL-4 into the manufacturing process or by priming manufactured CAR T products with IL-4 before infusion. Our findings provide insights into the mediators of durable CAR T therapy response and suggest potential therapeutic strategies to sustain long-term remission by boosting type 2 functionality in CAR T cells.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-07762-w","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T16:51:34Z","timestamp":1727283094000},"page":"702-711","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":134,"title":["Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission"],"prefix":"10.1038","volume":"634","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3977-3057","authenticated-orcid":false,"given":"Zhiliang","family":"Bai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6108-2017","authenticated-orcid":false,"given":"Bing","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan E.","family":"McClory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz Coutinho","family":"de Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Diorio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Gregoire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5490-4668","authenticated-orcid":false,"given":"Bo","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luojia","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziran","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Sferruzza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Kerr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alev","family":"Baysoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo G.","family":"Camara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-5005","authenticated-orcid":false,"given":"Sidi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6393-982X","authenticated-orcid":false,"given":"Li","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0241-3557","authenticated-orcid":false,"given":"Carl H.","family":"June","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7677-537X","authenticated-orcid":false,"given":"J. 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Bioinformatics 30, 523\u2013530 (2014).","journal-title":"Bioinformatics"}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-07762-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-07762-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-07762-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T21:11:15Z","timestamp":1729372275000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-07762-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,25]]},"references-count":45,"journal-issue":{"issue":"8034","published-print":{"date-parts":[[2024,10,17]]}},"alternative-id":["7762"],"URL":"https:\/\/doi.org\/10.1038\/s41586-024-07762-w","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,25]]},"assertion":[{"value":"28 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"R.F. is scientific founder and adviser for IsoPlexis, Singleron Biotechnologies and AtlasXomics. The interests of R.F. were reviewed and managed by Yale University Provost\u2019s Office in accordance with the University\u2019s conflict of interest policies. S.A.G. reports grants, personal fees and other support from Novartis and Vertex; grants from Jazz, Kite and Servier; personal fees and\/or scientific advisory boards from Roche, GSK, CBMG, Janssen\/J&J, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene and Cabaletta; in addition, S.A.G. has a patent for Toxicity management for antitumour activity of CARs, WO 2014011984 A1 issued. J.J.M. and C.H.J. hold patents related to CAR T cell manufacturing and biomarker discovery. C.H.J. is a scientific founder of Tmunity Therapeutics and DeCART Therapeutics, and is a member of the scientific advisory boards of AC Immune, BluesphereBio, Cabaletta, Carisma, Cartog-raphy, Cellares, Celldex, Decheng, Poseida, Verismo, WIRB-Copernicus and Ziopharm. L.T. is a co-founder, share-holder and advisor for Leman Biotech. The interests of L.T. were reviewed and managed by EPFL. S.C. is a co-founder of EvolveImmune, Cellinfinity, NumericGlobal and Chen Consulting, all unrelated to this study. The other authors declare no other competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}