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Recent advances have made the generation of T lymphocytes from induced pluripotent stem cells (iPSc) a promising therapeutic strategy. However, current approaches often fail to replicate the thymic niche, leading to impaired T cell generation. Here we address the production of functional mature iPSc-derived TECs supporting in vitro T cell generation. We optimize thymic lineage differentiation through an unbiased multifactorial experimental design. By modulating specific signaling pathways, we generate progenitors that mature into medullary and cortical TECs. Co-culture with primary hematopoietic progenitors in a 3D thymic organoid setup induces their differentiation into CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Importantly, thymic organoids support multilineage differentiation, with dendritic cell populations also emerging. Thus, the presented thymic organoid model provides a practical platform for studying thymic cellular interactions and thymopoiesis in vitro, and opens further research perspectives towards cell-based therapies.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-68675-y","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T11:35:34Z","timestamp":1769168134000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Combinatory differentiation of human induced pluripotent stem cells generates functional thymic epithelium driving dendritic cell and CD4\/CD8 T cell development"],"prefix":"10.1038","volume":"17","author":[{"given":"Nathan","family":"Provin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7239-4435","authenticated-orcid":false,"given":"Manon","family":"d\u2019Arco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Le Bozec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwan","family":"Kervagoret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Bruneau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Brusselle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3330-7530","authenticated-orcid":false,"given":"Cynthia","family":"Fourgeux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9613-5297","authenticated-orcid":false,"given":"Jeremie","family":"Poschmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Hulin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Maminirina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Baron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Saulquin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Guillonneau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3594-0353","authenticated-orcid":false,"given":"Laurent","family":"David","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1208-9677","authenticated-orcid":false,"given":"Matthieu","family":"Giraud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"68675_CR1","doi-asserted-by":"crossref","unstructured":"Miller, J. 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