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Abstract
Although natural killer cells (NK cells) were traditionally classified as members of the innate immune system, NK cells have recently been found also to be an important player in the adaptive immune systems. In this context, in vitro activation of NK cells by cytokines leads to generation of NK cells with memory-like properties characterized by increased interferon-γ (IFNγ) production. However, it remains to be defined whether these memory-like NK cells exist in vivo after cytokine activation. Furthermore, it is also unclear whether such memory-like NK cells induced in vivo by cytokines could have effective anti-leukemia response. To address these issues, we used an in vivo pre-activation and re-stimulation system that was able to produce NK cells with increased IFNγ secretion. It was found that after in vivo pre-activation and re-stimulation with interleukins (ILs), NK cells retained a state to produce increased amount of IFNγ. Of note, whereas this intrinsic capacity of enhanced IFNγ production after in vivo IL pre-activation and re-stimulation could be transferred to the next generation of NK cells and was associated with prolonged survival of the mice with acute lymphoid leukemia. Moreover, the anti-leukemia activity of these memory-like NK cells was associated with IFNγ production and up-regulation of NK cells activation receptor-NK Group 2 member D (NKG2D). Together, these findings argue strongly that in vivo IL pre-activation and re-stimulation is capable to induce memory-like NK cells as observed previously in vitro, which are effective against acute lymphoblastic leukemia, likely via NKG2D-dependent IFNγ production, in intact animals.
Highlights
As NK cells play a crucial role in immunosurveillance against tumor formation, NK cells and their receptors can be targeted in many therapeutic approaches [1]
In the positive-control group, NK cells isolated from the spleen of donor mice were preactivated with IL-12, IL-15, and IL-18 for overnight, after which cells were labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE) and adoptively transferred into the recipient mice; three weeks later, enriched NK cells harvested from the spleen of the recipient mice were re-stimulated in vitro with IL-12 and IL-15
The present study provided evidence supporting that a novel approach of in vivo IL pre-activation followed by in vivo re-stimulation once was able to induce memory-like properties of NK cells with enhanced IFNγ production, and significantly, these memory-like NK cells retained their enhanced capacity to produce IFNγ in mice for at least three weeks, despite the fact that the half life of NK cells is only about 7 days [18]
Summary
As NK cells play a crucial role in immunosurveillance against tumor formation, NK cells and their receptors can be targeted in many therapeutic approaches [1]. The classical concept of immunological memory solely applied to lymphocytes (i.e., T and B cells) has recently been challenged by the findings from the studies of NK cells, including that 1) antigen-specific NK memory cells can be induced by MCMV (mouse cytomegalovirus) infection; 2) NK memory cells can be induced by exposure to cytokines alone; and 3) liver-restricted NK memory cells display highly antigen-specific recall immune responses [2] In this context, activation of NK cells by cytokines alone leads to generation of NK cells with memory-like properties characterized by increased IFNγ production [3]. As NK cells constitutively express IFNγ transcripts [6], it is most likely that those epigenetic modifications appear at the loci responsible for post-transcriptional or posttranslational up-regulation of this cytokine
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