Journal
EXPERIMENTAL HEMATOLOGY
Volume 36, Issue 5, Pages 598-608Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.exphem.2008.01.001
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Funding
- NCI NIH HHS [P01 CA065493-110010, P01-CA-65493, P01 CA065493] Funding Source: Medline
- NHLBI NIH HHS [R01 HL055417, R01 HL055417-12, R01-HL-55417] Funding Source: Medline
- NIAID NIH HHS [R01 AI050656, R01-AI-50656] Funding Source: Medline
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Objective. Human natural killer (NK) cell maturation involves the orderly acquisition of NK cell receptors. Our aim was to understand how stromal interactions and cytokines are important in this developmental process. Materials and Methods. Human umbilical cord blood (UCB) CD34(+)/Lin(-)/CD38(-) cells were cultured on two murine stromal cell lines (AFT024 and EL08-ID2) in a switch culture to study NK cell development. Results. When human progenitors were cultured on AFT024 with interleukin (IL)-3 and FIB ligand (Flt3L) in the absence of interleukin (IL)-15, NK cell differentiation occurred, albeit at low frequency. These conditions favored the accumulation of CD56(-) NK cell precursors (CD34(+)CD7(-), CD34(+)CD7(+), and CD34(-)CD7(+) cells), which are populations rare in adult blood A but abundant in fresh UCB. In secondary culture, addition of IL-3 or IL-3 + Flt3L to IL-15 increased the absolute number of CD56(+) NK cells from precursors and the acquisition of CD94 and killer immunoglobulin-like receptors (KIR). To further explore the microenvironment in early NK cell maturation, a cell line derived from murine embryonic liver (EL08-ID2) was studied. NK cell development and KIR acquisition was superior with EL08-ID2, which supported the differentiation of NK cell precursors, NK cell commitment, and proliferation. Conclusion. Although the earliest events in NK cell maturation do not require exogenous human IL-15, it is required at a later stage of NK cell commitment. At a minimum, murine stroma, IL-3, and Flt3L are required to recapitulate early NK cell development and differentiation into distinct NK cell precursors. EL08-1D2 induces KIR acquisition suggesting that extrinsic signals in NK cell development are conserved between mouse and man. (C) 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
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