{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T04:33:57Z","timestamp":1787978037838,"version":"build-2784847793"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005677","name":"Jose Carreras Leukamie-Stiftung","doi-asserted-by":"publisher","award":["22R\/2019"],"award-info":[{"award-number":["22R\/2019"]}],"id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["444949889, 413490537"],"award-info":[{"award-number":["444949889, 413490537"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Blinatumomab (BLN) is a bispecific T-cell engager that has revolutionized the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), significantly improving outcomes in both adults and children. By simultaneously binding to CD19 on B cells and CD3 on T cells, BLN triggers target cell-dependent T-cell activation, resulting in the cytolysis of CD19\n                      <jats:sup>+<\/jats:sup>\n                      BCP-ALL cells. Despite the remarkable clinical advancements achieved with BLN, the immunological mechanisms underlying treatment response or failure remain poorly characterized. \u03b3\u03b4 T cells are attractive candidates for adoptive T-cell therapy due to potent cytotoxicity, capacity to present antigens, broad lysis of different tumor entities, and low alloreactivity. Because \u03b3\u03b4 T cells can also be redirected by BLN, we systematically studied BLN-driven effector functions\n                      <jats:italic>in vitro<\/jats:italic>\n                      in conventional \u03b1\u03b2 and unconventional \u03b3\u03b4 T cells from healthy donors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      We evaluated cytotoxicity and cytokine\/effector release in freshly isolated and\n                      <jats:italic>in vitro<\/jats:italic>\n                      -expanded \u03b1\u03b2 and \u03b3\u03b4 T cells from healthy adults against CD19\n                      <jats:sup>+<\/jats:sup>\n                      BCP-ALL cell lines (NALM-6, HAL-01), and profiled dynamic phenotypic alterations by multiparametric flow cytometry.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CD19\n                      <jats:sup>+<\/jats:sup>\n                      targets were consistently reduced in the presence of BLN. Freshly isolated \u03b1\u03b2, especially CD8\n                      <jats:sup>+<\/jats:sup>\n                      , displayed superior BLN-mediated effector functions as compared to \u03b3\u03b4 T cells, with donor-dependent variability in \u03b3\u03b4 killing. Notably, zoledronate-expanded V\u03b39V\u03b42 \u03b3\u03b4 T-cell lines achieved cytotoxicity comparable to PHA-expanded \u03b1\u03b2 cells. However, \u03b3\u03b4 T-cell-killing benefited from higher BLN concentration when challenged with high tumor load. In these\n                      <jats:italic>in vitro<\/jats:italic>\n                      healthy-donor T-cell cultures, BLN induced CD3 down-modulation in \u03b1\u03b2 T cells but not in \u03b3\u03b4 T cells, and \u03b1\u03b2 cultures released higher soluble Fas ligand, findings consistent with stronger early activation and suggestive of increased susceptibility to activation-associated apoptosis\/AICD. Exploratory targeted single-cell transcriptomics (one donor) supported a pronounced activation\/exhaustion program in \u03b1\u03b2 T cells and a comparatively stable effector-memory profile with low checkpoint expression in \u03b3\u03b4 T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Together, these\n                      <jats:italic>in vitro<\/jats:italic>\n                      data reveal subset-specific BLN responses and support the hypothesis that ex vivo-expanded V\u03b39V\u03b42 \u03b3\u03b4 T cells could complement BLN-mediated cytotoxicity, particularly under conditions of higher CD19 density and lower target burden. These findings provide a mechanistic framework for future testing of \u03b3\u03b4 T-cell\/BLN combination strategies in patient-derived models and clinical studies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1739493","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T06:48:58Z","timestamp":1770360538000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Blinatumomab-driven T-cell activation in \u03b1\u03b2 and \u03b3\u03b4 T-cell subsets: insights from in vitro assays"],"prefix":"10.3389","volume":"17","author":[{"given":"Miriam","family":"Kelm","sequence":"first","affiliation":[{"name":"Medical Department II, Hematology and Oncology, Christian-Albrechts University of Kiel and University Hospital Schleswig-Holstein","place":["Kiel, 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