Human NK cells of mice with reconstituted human immune system components require pre-activation to acquire functional competence.

To investigate human natural killer (NK)– cell reactivity in vivo we have reconstituted human immune system components by transplantation of human hematopoietic progenitor cells into NODscid IL2Rnull mice. We demonstrate here that this model allows the development of all NK-cell subsets that are also found in human adult peripheral and cord blood, including NKp46CD56 NK cells. Similar to human cord blood, NK cells from these reconstituted mice require preactivation by interleukin-15 to reach the functional competence of human adult NK cells. Mainly the terminally differentiated CD16 NK cells demonstrate lower reactivity without this stimulation. After preactivation, both CD16 and CD16 NK cells efficiently produce interferon- and degranulate in response to stimulation with NK cell–susceptible targets, including K562 erythroleukemia cells. NK-cell lines, established from reconstituted mice, demonstrate cytotoxicity against this tumor cell line. Importantly, preactivation can as well be achieved by bystander cell maturation via poly I:C stimulation in vitro and injection of this maturation stimulus in vivo. Preactivation in vivo enhances killing of human leukocyte antigen class I negative tumor cells after their adoptive transfer. These data suggest that a functional, but resting, NK-cell compartment can be established in immune-compromised mice after human hematopoietic progenitor cell transfer.