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

Rose C. Beck, Mallika Padival, David Yeh, Justine Ralston, Kenneth R Cooke, John B. Lowe

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1026-1037
Number of pages12
JournalBiology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
Volume15
Issue number9
DOIs
StatePublished - Sep 2009
Externally publishedYes

Fingerprint

Hematopoietic Stem Cells
Fetal Blood
Natural Killer Cells
Ligands
Aptitude
Stromal Cells
KIR Receptors
Notch Receptors
Cell Line
Interleukin-15
Interleukin-7
Human Development
Interferons
Blood Cells
T-Lymphocytes

Keywords

  • Cell therapy
  • Natural killer cell
  • Notch
  • Umbilical cord blood

ASJC Scopus subject areas

  • Transplantation
  • Hematology

Cite this

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title = "The Notch Ligands Jagged2, Delta1, and Delta4 Induce Differentiation and Expansion of Functional Human NK Cells from CD34+ Cord Blood Hematopoietic Progenitor Cells",
abstract = "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.",
keywords = "Cell therapy, Natural killer cell, Notch, Umbilical cord blood",
author = "Beck, {Rose C.} and Mallika Padival and David Yeh and Justine Ralston and Cooke, {Kenneth R} and Lowe, {John B.}",
year = "2009",
month = "9",
doi = "10.1016/j.bbmt.2009.06.002",
language = "English (US)",
volume = "15",
pages = "1026--1037",
journal = "Biology of Blood and Marrow Transplantation",
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T1 - The Notch Ligands Jagged2, Delta1, and Delta4 Induce Differentiation and Expansion of Functional Human NK Cells from CD34+ Cord Blood Hematopoietic Progenitor Cells

AU - Beck, Rose C.

AU - Padival, Mallika

AU - Yeh, David

AU - Ralston, Justine

AU - Cooke, Kenneth R

AU - Lowe, John B.

PY - 2009/9

Y1 - 2009/9

N2 - 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.

AB - 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.

KW - Cell therapy

KW - Natural killer cell

KW - Notch

KW - Umbilical cord blood

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