Cytokine requirements for the growth and development of mouse NK cells in vitro

Natural killer (NK) cells arise from immature progenitors present in fetal tissues and adult bone marrow, but the factors responsible for driving the proliferation and differentiation of these progenitors are poorly understood. Mouse NK cells had previously been thought not to ex- press interleukin (IL)-2R chains, but we show here that immature and mature mouse NK cells express IL-2R chain mRNA and that low levels of IL-2R chains can be detected on the surface of immature and mature NK cells provided they are cultured in the absence of IL-2. Despite their po- tential expression of high-affinity IL-2 receptors, immature NK cells only proliferate if IL-2 is present at extremely high concentrations. Surpris- ingly, IL-15 can also only support the growth of immature NK cells at high, presumably nonphysi- ological concentrations. Although NK cells express mRNA for the high-affinity IL-15R chain, they also express a variety of alternately spliced tran- scripts whose protein products could potentially disrupt signaling through IL-15 receptors. The re- quirement for high concentrations of IL-2 and IL-15 suggests that if these cytokines play any role in the proliferative expansion of NK cells in vivo, they act indirectly via other cells or in cooperation with other factors. In support of the latter possibil- ity, we report that the recently described cytokine IL-21 can markedly enhance the proliferation of immature (and mature) NK cells in the presence of doses of IL-2 and IL-15 that by themselves have little growth-promoting activity. J. Leukoc. Biol. 74: 000-000; 2003.