The Notch Ligands Jagged2, Delta1, and Delta4 Induce Differentiation and Expansion of Functional Human NK Cells from CD34+ Cord Blood Hematopoietic Progenitor Cells

• Published in: Biology of blood and marrow transplantation 2009-09, Vol.15 (9), p.1026-1037
• Main Authors: Beck, Rose C, Padival, Mallika, Yeh, David, Ralston, Justine, Cooke, Kenneth R, Lowe, John B
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD34 - biosynthesis; Antigens, CD34 - immunology; Bone Marrow Cells - cytology; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; CD56 Antigen - biosynthesis; CD56 Antigen - immunology; Cell Differentiation - immunology; Cell Line; Cell therapy; Cells, Cultured; Hematology, Oncology and Palliative Medicine; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - metabolism; Humans; Immunophenotyping; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Intracellular Signaling Peptides and Proteins; Jagged-2 Protein; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Ligands; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Natural killer cell; Notch; Receptors, Notch - immunology; Stromal Cells - cytology; Stromal Cells - immunology; Stromal Cells - metabolism; Transduction, Genetic; Umbilical cord blood
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2009.06.002

Notch receptor signaling is required for T cell development, but its role in natural killer (NK) cell development is poorly understood. We compared the ability of the 5 mammalian Notch ligands (Jagged1, Jagged2, Delta1, Delta3, or Delta4) to induce NK cell development from human hematopoietic progenitor cells (HPCs). CD34+ HPCs were cultured with OP9 stromal cell lines transduced with 1 of the Notch ligands or with OP9 stromal cells alone, in the presence of IL-7, Flt3L, and IL-15. Differentiation and expansion of CD56+ CD3− cells were greatly accelerated in the presence of Jagged2, Delta-1, or Delta-4, versus culture in the absence of ligand or in the presence of Jagged1 or Delta3. At 4 weeks, cultures containing Jagged2, Delta1, or Delta4 contained 80% to 90% NK cells, with the remaining cells being CD33+ myelogenous cells. Notch-induced NK (N-NK) cells resembled CD56bright NK cells in that they were CD16− , CD94− , CD117+ , and killer immunoglobulin-like receptors (KIR− ). They also expressed NKp30, NKp44, NKp46, 2B4, and DNAM-1, with partial expression of NKG2D. The N-NK cells displayed cytotoxic activity against the K562 and RPMI-8226 cell lines, at levels similar to activated peripheral blood (PB) NK cells, although killing of Daudi cells was not present. N-NK cells were also capable of interferon (IFN)-γ secretion. Thus, Notch ligands have differential ability to induce and expand immature, but functional, NK cells from CD34+ HPCs. The use of Notch ligands to generate functional NK cells in vitro may be significant for cellular therapy purposes.