Role of Interleukin-2 (IL-2), IL-7, and IL-15 in Natural Killer Cell Differentiation From Cord Blood Hematopoietic Progenitor Cells and From γc Transduced Severe Combined Immunodeficiency X1 Bone Marrow Cells

• Published in: Blood 1996-11, Vol.88 (10), p.3901-3909
• Main Authors: Cavazzana-Calvo, M., Hacein-Bey, S., de Saint Basile, G., De Coene, C., Selz, F., Le Deist, F., Fischer, A.
• Format: Article
• Language: English
• Subjects: Antibody-Dependent Cell Cytotoxicity; Biological and medical sciences; Bone Marrow - pathology; Cell Differentiation - drug effects; Colony-Forming Units Assay; Fetal Blood - cytology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infant; Interleukin-15 - pharmacology; Interleukin-2 - pharmacology; Interleukin-7 - pharmacology; Killer Cells, Natural - cytology; Male; Medical sciences; Point Mutation; Polymerase Chain Reaction; Proviruses - genetics; Receptors, Cytokine - deficiency; Receptors, Cytokine - genetics; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - pathology; Transfection
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V88.10.3901.bloodjournal88103901

Natural killer (NK) cells are characterized by their ability to mediate spontaneous cytotoxicity against susceptible tumor cells and infected cells. They differentiate from hematopoietic progenitor cells. Patients with X-linked severe combined immunodefiency (SCID X1) carry mutations in the γc cytokine receptor gene that result in lack of both T and NK cells. To assess the role of interleukin-2 (IL-2), IL-7, and IL-15 cytokines, which share γc receptor subunit, in NK cell differentiation, we have studied NK cell differentiation from cord blood 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 efficiently induced CD34 (+) CD7 (+) cord blood cells to proliferate and mature into NK cells, while the latter was also able to induce NK cell differentiation from more immature CD34 (+) CD7 (-) cord blood cells. NK cells expressed CD56 and efficiently killed K562 target cells. These results show that IL-15 could play an important role in the maturation of NK cell from cord blood progenitors. Following ret-roviral-mediated gene transfer of γc into SCID X1 bone marrow progenitors, it was possible to reproduce a similar pattern of NK cell differentiation in two 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 γc chain transduces major signal(s) involved in NK cell differentiation from hematopoietic progenitor cells and that IL-15 interaction with γc is involved in this process at an earlier step than IL-2/IL-7 interactions of γc are. It also shows that gene transfer into hematopoietic progenitor cells could potentially restore NK cell differentiation in SCID X1 patients.