Interleukin (IL)-18 Binding Protein Deficiency Disrupts Natural Killer Cell Maturation and Diminishes Circulating IL-18

Abstract

The cytokine interleukin (IL)-18 is a crucial amplifier of natural killer (NK) cell function. IL-18 signaling is regulated by the inhibitory effects of IL-18 binding protein (IL-18BP). Using mice deficient in IL-18BP (IL-18BPKO), we investigated the impact of mismanaged IL-18 signaling on NK cells. We found an overall reduced abundance of splenic NK cells in the absence of IL-18BP. Closer examination of NK cell subsets in spleen and bone marrow using CD27 and CD11b expression revealed that immature NK cells were increased in abundance, while the mature population of NK cells was reduced. Also, NK cells were polarized to greater production of TNF-α, while dedicated IFN-γ producers were reduced. A novel subset of IL-18 receptor α− NK cells contributed to the expansion of immature NK cells in IL-18BPKO mice. Splenocytes cultured with IL-18 resulted in alterations similar to those observed in IL-18BP deficiency. NK cell changes were associated with significantly reduced levels of circulating plasma IL-18. However, IL-18BPKO mice exhibited normal weight gain and responded to LPS challenge with a >10-fold increase in IFN-γ compared to wild type. Finally, we identified that the source of splenic IL-18BP was among dendritic cells/macrophage localized to the T cell-rich regions of the spleen. Our results demonstrate that IL-18BP is required for normal NK cell abundance and function and also contributes to maintaining steady-state levels of circulating IL-18. Thus, IL-18BP appears to have functions suggestive of a carrier protein, not just an inhibitor.

A new checkpoint for Natural Killer cell activation

“…IL-18BP-null mice thus could be expected to present with a NK cell phenotype similar to Il1r8 À/À mice, however, Il18 bp À/À mice were recently shown to have the opposite NK cell maturation phenotype to Il1r8 À/À mice with an accumulation of immature (CD11b À ) and reduction in mature KLRG1 + NK cells. 4 In the same study, NK cells from Il18 À/À mice displayed a normal NK cell maturation, consistent with our earlier study 5 questioning the direct role of IL-18 in NK cell maturation. Consistently, both Il18 bp À/À and Il1r8 À/À mice presented with significantly elevated IFN-c levels when challenged with pathogens/tumor supporting the notion that IL-18 reduces the activation threshold and primes NK cells in vivo.…”

“…IL‐18 bioavailability is also negatively regulated by IL‐18 binding protein (IL‐18BP), which sequesters free IL‐18. IL‐18BP‐null mice thus could be expected to present with a NK cell phenotype similar to Il1r8 −/− mice, however, Il18 bp −/− mice were recently shown to have the opposite NK cell maturation phenotype to Il1r8 −/− mice with an accumulation of immature (CD11b − ) and reduction in mature KLRG1 + NK cells . In the same study, NK cells from Il18 −/− mice displayed a normal NK cell maturation, consistent with our earlier study questioning the direct role of IL‐18 in NK cell maturation.…”

The family of the interleukin‐1 receptors

“…While the IL‐18‐inhibitory capacity of IL‐18BP is widely acknowledged, there are suggestions of additional distinct activities, e.g. as an alternative receptor for IL‐18 in the brain and as a transporter of IL‐18 to maintain physiological rates of NK cell maturation …”

“…In circulation, the majority of IL‐18 is bound to IL‐18BP, which acts as inhibitor (see Sections and ). However, there is evidence that IL‐18BP may rather act as carrier of IL‐18, as genetic deletion of IL‐18BP results in decreased circulating levels of IL‐18 and increased local effects of IL‐18 . Indeed, as the affinity of human IL‐18 for IL‐18BP is 0.4 nM and that for IL‐1R5 has been reported between 3 and 94 nM in different systems/cells, it seems obvious that in steady‐state conditions IL‐18 is more abundantly associated to IL‐18BP.…”

“…as an alternative receptor for IL-18 in the brain 104 and as a transporter of IL-18 to maintain physiological rates of NK cell maturation. 105…”