ROLE OF INTERLEUKIN-2 (IL-2), IL-7, AND IL-15 IN NATURAL-KILLER-CELL DIFFERENTIATION FROM CORD-BLOOD HEMATOPOIETIC PROGENITOR CELLS AND FROM GAMMA-C TRANSDUCED SEVERE COMBINED IMMUNODEFICIENCY-XI BONE-MARROW CELLS

Natural killer (NK) cells are characterized by their ability to mediat e spontaneous cytotoxicity against susceptible tumor cells and infecte d cells. They differentiate from hematopoietic progenitor cells. Patie nts with X-linked severe combined immunodeficiency (SCID X1) carry mut ations in the gamma c cytokine receptor gene that result in lack of bo th T and NK cells. To assess the role of interleukin-2 (IL-2), IL-7, a nd IL-15 cytokines, which share gamma c receptor subunit, in NK cell d ifferentiation, we have studied NK cell differentiation from cord bloo d CD34 (+) cells in the presence of either stem cell factor (SCF), IL- 2, and IL-7 or SCF and IL-15. The former cytokine combination efficien tly induced CD34 (+) CD7 (+) cord blood cells to proliferate and matur e into NK cells, while the latter was also able to induce NK cell diff erentiation from more immature CD34 (+) CD7 (-) cord blood cells. NK c ells expressed CD56 and efficiently killed K562 target cells. These re sults show that IL-15 could play an important role in the maturation o f NK cell from cord blood progenitors. Following retroviral-mediated g ene transfer of gamma c into SCID X1 bone marrow progenitors, it was p ossible to reproduce a similar pattern of NK cell differentiation in t wo SCID-X1 patients with SCF + IL-2 + IL-7 and more efficiently in one of them with SCF + IL-15. These results strongly suggest that the gam ma c chain transduces major signal(s) involved in NK cell differentiat ion from hematopoietic progenitor cells and that IL-15 interaction wit h gamma c is involved in this process at an earlier step than IL-2/IL- 7 interactions of gamma c are. It also shows that gene transfer into h ematopoietic progenitor cells could potentially restore NK cell differ entiation in SCID X1 patients. (C) 1996 by The American Society of Hem atology.