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With the advent of the artificial thymic organoid (ATO) method, the in vitro differentiation of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells from iPSCs has also become feasible. CD4\u207a T cells have shown superior longevity, resistance to exhaustion, and helper functions in primary settings, but whether iPSC-derived CD4\u207a T cells retain these features remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, CD4\u207a T cells were differentiated from human iPSCs using the ATO system. Primary T cells served as controls to evaluate the phenotypic and activation features of iPSC-derived CD4\u207a and CD8\u207a T cells. To assess antitumor function, we generated CD19-BB\u03b6 CAR-iPSC-T cells and employed a hematologic malignancy model using NALM6 acute lymphoblastic leukemia (ALL) cells. Both short-term and long-term cytotoxicity assays were conducted to compare iPSC-derived CD4\u207a and CD8\u207a T cells in terms of killing efficiency, cytokine secretion, persistence, exhaustion phenotype, and proliferative capacity. The helper function of iPSC-derived CD4\u207a T cells toward CD8\u207a T cells was further evaluated by Ki-67 staining and proliferation assays. Statistical analyses were performed using GraphPad Prism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our study demonstrated that iPSC-derived CD4\u207a T cells exhibited both helper- and cytotoxic-like features. Compared with iPSC-derived CD8\u207a T cells or CD4\u207a\/CD8\u207a mixtures, iPSC-derived CD4\u207a T cells showed superior proliferation, cytokine secretion, and sustained cytotoxicity following CAR transduction. They also promoted the expansion of iPSC-derived CD8\u207a T cells and displayed helper-like functions with increased resistance to exhaustion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Although not identical to primary CD4\u207a T cells, iPSC-derived CD4\u207a T cells recapitulated key functional advantages, especially sustained antitumor activity, supporting their value as a renewable, off-the-shelf source for next-generation CAR-T therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s41232-025-00402-4","type":"journal-article","created":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T01:41:44Z","timestamp":1767490904000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Adaptive-like CAR-iPSC-CD4\u207a T cells outperform CD8\u207a counterparts in sustained ALL control"],"prefix":"10.1186","volume":"46","author":[{"given":"Qingyi","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoichi","family":"Iriguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsutaka","family":"Minagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2291-4586","authenticated-orcid":false,"given":"Shin","family":"Kaneko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,3]]},"reference":[{"issue":"7","key":"402_CR1","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1016\/j.tibtech.2023.02.003","volume":"41","author":"D Xue","year":"2023","unstructured":"Xue D, Lu S, Zhang H, Zhang L, Dai Z, Kaufman DS, et al. 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