In vitro–differentiated T/natural killer–cell progenitors derived from human CD34+ cells mature in the thymus

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−/−γc−/− mice, these cells selectively home to the thymus and differentiate toward surface T-cell receptor–αβ+ 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.