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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>We previously established a feeder-free cell therapy platform for the <jats:italic>ex vivo<\/jats:italic> generation of lymphoid-primed progenitors using immobilized Delta-like ligand 4 (DLL4). <jats:italic>In vivo<\/jats:italic> studies demonstrated that adoptive transfer of these progenitors accelerates T cell reconstitution following thymic engraftment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>To further explore the full therapeutic potential of this cell product, we performed a comprehensive molecular and phenotypic characterization using single cell RNA sequencing and mass cytometry analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analysis revealed the presence of distinct cell subsets within the cellular product characterized mainly by commitment to lymphoid lineages. Using integrated transcriptomic analyses to compare these <jats:italic>ex vivo<\/jats:italic>-generated progenitors to <jats:italic>in vivo<\/jats:italic> human thymocytes, we revealed strong similarities with early stages of T cell development, underscoring the physiological relevance of our system. We also delineated two distinct developmental trajectories within the CD7<jats:sup>+<\/jats:sup> progenitor population: a T cell-oriented path, marked by CD5 upregulation, and an innate lymphoid cell (ILC)-oriented branch, identified by CD161 expression and an ILC-like gene signature. Despite these lineage predispositions, both subsets demonstrated plasticity, retaining the ability to differentiate into both T cells and natural killer (NK) cells <jats:italic>in vitro<\/jats:italic>. Additionally, in our experimental setting, we observed that BCL11B, a transcription factor essential for T cell commitment, regulates negatively myeloid cell differentiation while preserving the potential for NK cell development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings underscore the versatility of DLL4-based lymphoid progenitors in generating either T cells or ILCs in response to environmental cues. This research paves the way for innovative cell therapy approaches to treat immune deficiencies and cancer- and age-related immune dysfunctions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1617707","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T05:36:40Z","timestamp":1753249000000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ex vivo-generated lymphoid progenitors encompass both T cell and innate lymphoid cell fates"],"prefix":"10.3389","volume":"16","author":[{"given":"Pierre","family":"Gaudeaux","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliette","family":"Paillet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monah","family":"Abou Alezz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ranjita Devi","family":"Moirangthem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Cascione","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Martin Corredera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne-Catherine","family":"Dolens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrien","family":"De Mulder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imke","family":"Velghe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bart","family":"Vandekerckhove","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marieke","family":"Lavaert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"No\u00e9mie","family":"Robil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aur\u00e9lien","family":"Corneau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanem","family":"Sadek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pauline","family":"Rault","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akshay","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"de la Grange","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank J. 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