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 Blood, 1 May 2005, Vol. 105, No. 9, pp. 3521-3527.
Prepublished online as a Blood First Edition Paper on January 13, 2005; DOI 10.1182/blood-2004-11-4237.

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HEMATOPOIESIS

Jagged2 promotes the development of natural killer cells and the establishment of functional natural killer cell lines

Sarah L. DeHart, Marc J. Heikens, and Schickwann Tsai

From the Division of Hematology, Department of Medicine, University of Utah, Salt Lake City, UT.

Emerging evidence indicates that Notch receptors and their ligands play important roles in the development of T cells and B cells. However, little is known about their possible roles in the development of other lymphoid cells. Here we demonstrate that Jagged2, a Notch ligand, stimulates the development of natural killer (NK) cells from Lin- Sca-1+ c-kit+ hematopoietic stem cells. Our culture system supports NK cell development for 2 to 3 months, often leading to the establishment of continuous NK cell lines. The prototype of such cell lines is designated as KIL. KIL depends on interleukin-7 for survival and proliferation and is NK1.1+ CD3- TCR{alpha}{beta}- TCR{delta}{gamma}- CD4- CD8- CD19- CD25+ CD43+ CD45+ CD49b- CD51+ CD94+ NKG2D+ Mac-1-/low B220- c-kit+ perforin I+ granzyme B+ Notch-1+, and cytotoxic. Like normal natural killer cells, the T-cell receptor-{beta} loci of KIL remain in the germ-line configuration. In response to interleukin-2, KIL proliferates extensively (increasing cell number by approximately 1010-fold) and terminally differentiates into adherent, hypergranular NK cells. Our findings indicate that Jagged2 stimulates the development of natural killer cells and the KIL cell line preserves most properties of the normal NK precursors. As such, KIL provides a valuable model system for NK cell research.


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