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J Leukoc Biol. 2014 Dec;96(6):1165-75. doi: 10.1189/jlb.1TA0214-121RR. Epub 2014 Aug 25.

Technical advance: ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells.

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Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center, and
Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center, and.
Department of Toxicogenomics, School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.


The efficacy of donor HSCT is partly reduced as a result of slow post-transplantation immune recovery. In particular, T cell regeneration is generally delayed, resulting in high infection-related mortality in the first years post-transplantation. Adoptive transfer of in vitro-generated human T cell progenitors seems a promising approach to accelerate T cell recovery in immunocompromised patients. AA may enhance T cell proliferation and differentiation in a controlled, feeder-free environment containing Notch ligands and defined growth factors. Our experiments show a pivotal role for AA during human in vitro T cell development. The blocking of NOS diminished this effect, indicating a role for the citrulline/NO cycle. AA promotes the transition of proT1 to proT2 cells and of preT to DP T cells. Furthermore, the addition of AA to feeder cocultures resulted in development of DP and SP T cells, whereas without AA, a preT cell-stage arrest occurred. We conclude that neither DLL4-expressing feeder cells nor feeder cell conditioned media are required for generating DP T cells from CB and G-CSF-mobilized HSCs and that generation and proliferation of proT and DP T cells are greatly improved by AA. This technology could potentially be used to generate T cell progenitors for adoptive therapy.


DLL4 protein; T cell precursor; adoptive cellular immunotherapy; transplantation

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