Active form of Notch imposes T cell fate in human progenitor cells.
The crucial role of Notch signaling in cell fate decisions in hematopoietic lineage and T lymphocyte development has been well established in mice. Overexpression of the intracellular domain of Notch mediates signal transduction of the protein. By retroviral transduction of this constitutively active truncated intracellular domain in human CD34+ umbilical cord blood progenitor cells, we were able to show that, in coculture with the stromal MS-5 cell line, depending on the cytokines added, the differentiation toward CD19+ B lymphocytes was blocked, the differentiation toward CD14+ monocytes was inhibited, and the differentiation toward CD56+ NK cells was favored. The number of CD7+cyCD3+ cells, a phenotype similar to T/NK progenitor cells, was also markedly increased. In fetal thymus organ culture, transduced CD34+ progenitor cells from umbilical cord blood cells or from thymus consistently generated more TCR-gammadelta T cells, whereas the other T cell subpopulations were largely unaffected. Interestingly, when injected in vivo in SCID-nonobese diabetic mice, the transduced cells generated ectopically human CD4+CD8+ TCR-alphabeta cells in the bone marrow, cells that are normally only present in the thymus, and lacked B cell differentiation potential. Our results show unequivocally that, in human, Notch signaling inhibits the monocyte and B cell fate, promotes the T cell fate, and alters the normal T cell differentiation pathway compatible with a pretumoral state.
De Smedt
Magda
M
Department of Clinical Chemistry, Microbiology, and Immunology, University of Ghent, Ghent University Hospital, Ghent, Belgium.
Reynvoet
Katia
K
Kerre
Tessa
T
Taghon
Tom
T
Verhasselt
Bruno
B
Vandekerckhove
Bart
B
Leclercq
Georges
G
Plum
Jean
J
D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D006131:Growth Inhibitors / Q000378:metabolism / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000166:cytology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D022423:Myeloid Cells / Q000166:cytology; D009924:Organ Culture Techniques; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis; D051880:Receptors, Notch; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014161:Transduction, Genetic
D018952:Antigens, CD34; D006131:Growth Inhibitors; D008565:Membrane Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D051880:Receptors, Notch; D015534:Trans-Activators