Differential effects of interleukin-3, interleukin-7, interleukin 15, and granulocyte-macrophage colony-stimulating factor in the generation of natural killer and B cells from primitive human fetal liver progenitors

Objective. The regulatory roles of a number of early-acting growth factors on the generation of natural killer (NK) cells and B cells from primitive p rogenitors were studied. Experiments focused on the contributions of granul ocyte-macrophage colony-stimulates factor (GM-CSF) and interleukin-1 (IL-3) to the regulation of the early events of lymphopoiesis, Materials and Methods. Two progenitor populations isolated from human fetal liver were studied, CD38 CD34+ (+)lineage(-) (Lin(-)) cells (candidate hem atopoietic stem cells [HSCs]) and the more mature CD38(1) CD34(+ +)Lin(-) c ells. The effects of different cytokines on the generation of CD56(+)CD3(-) NK cells and CD19(+) B cells were studied in serum-deprived cultures in th e absence of stroma. Results. NK cells generated in vitro were able to kill NK-sensitive target cells, expressed NK-associated marker CD161 (NKR-P1A), but exhibited little or no expression of CD2, CD8, CD16, CD94/NKG2A, or killer cell inhibitory receptors (KIRs), Among the cytokine combinations tested, kit ligand (KL) a nd IL-15 provided the best conditions for generating CD56(+) NK cells from CD38(+)CD34(+ +)Lin(-) cells. However, either flk-2/flt3 ligand (FL), CM-CS F, IL-3, or IL-7 could partially substitute KL. All of these cytokines also supported the growth of NK-cell progenitors from candidate HSC, with the c ombination of IL-15, KL, GM-CSF, and PL generating the greatest number of C D56(+) cells, B cells were generated from both progenitor populations in re sponse to the combined effects of KL, FL, and IL-7, Both B and NK cells wer e generated with the further addition of IL-15 to these cultures. The in vi tro generated B cells were CD10(+), CD19(+), HLA-DR+, HLA-DQ(+), and some w ere CD20(+), but no cytoplasmic or surface immunoglobulin M expression was observed, In contrast with NK lymphopoiesis, GM-CSF, IL-3, and IL-15 had no effect on the generation of B cells from CD38(-)CD34(+ +)Lin(-) cells, and GM-CSF inhibited B-cell generation from CD38(+)CD34(+) (+)Lin(-) progenito rs. Conclusion. These findings indicate a differential regulation of NK and B l ymphopoiesis beginning in the early stages of hematopoiesis as exemplified by the distinctive roles of IL-7, IL-15, GM-CSF, and IL-3, (C) 2000 Interna tional Society for Experimental Hematology, Published by Elsevier Science I nc.