title: In vitro-differentiated T/natural killer-cell progenitors derived from human CD34+ cells mature in the thymus.
abstract: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a treatment option for patients with hematopoietic malignancies that is hampered by treatment-related morbidity and mortality, in part the result of opportunistic infections, a direct consequence of delayed T-cell recovery. Thymic output can be improved by facilitation of thymic immigration, known to require precommitment of CD34(+) cells. We demonstrate that Delta-like ligand-mediated predifferentiation of mobilized CD34(+) cells in vitro results in a population of thymocyte-like cells arrested at a T/natural killer (NK)-cell progenitor stage. On intrahepatic transfer to Rag2(-/-)gamma(c)(-/-) mice, these cells selectively home to the thymus and differentiate toward surface T-cell receptor-alphabeta(+) mature T cells considerably faster than animals transplanted with noncultured CD34(+) cells. This finding creates the opportunity to develop an early T-cell reconstitution therapy to combine with HSCT.
authors.affiliation: Department of Internal Medicine, Division of Haematology, Maastricht University Medical Center, Maastricht, The Netherlands;
authors.forename: Bob
authors.initials: B
authors.lastname: Meek
authors.forename: Silvie
authors.initials: S
authors.lastname: Cloosen
authors.forename: Chiara
authors.initials: C
authors.lastname: Borsotti
authors.forename: Catharina H M J
authors.initials: CH
authors.lastname: Van Elssen
authors.forename: Joris
authors.initials: J
authors.lastname: Vanderlocht
authors.forename: Melanie C A
authors.initials: MC
authors.lastname: Schnijderberg
authors.forename: Marjolein W M
authors.initials: MW
authors.lastname: van der Poel
authors.forename: Bas
authors.initials: B
authors.lastname: Leewis
authors.forename: Reinout
authors.initials: R
authors.lastname: Hesselink
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.forename: Yoshimoto
authors.initials: Y
authors.lastname: Katsura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.forename: Wilfred T V
authors.initials: WT
authors.lastname: Germeraad
authors.forename: Gerard M J
authors.initials: GM
authors.lastname: Bos
mesh_terms: D000818:Animals; D018952:Antigens, CD34; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: D018952:Antigens, CD34; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse