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.