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.
Highlights
Cytokines are capable of heavily modulating the function and phenotype of immune cells
Splenocyte numbers were similar among IL-18BPKO and wild type (WT) mice (Figure 1B), we observed both a decrease in proportion and number of natural killer (NK) cells among IL-18BPKO mice compared to WT (Figures 1C,D)
Our results reveal that the IL-18 binding protein (IL-18BP) plays a key role in NK cell maturation and function
Summary
Cytokines are capable of heavily modulating the function and phenotype of immune cells. In the case of natural killer (NK) cells, several cytokines have been shown to induce a profound impact on their attributes [reviewed in Ref. Interleukin-18 (IL-18, interferon-γ-inducing factor) is unique, in part, due to its ubiquitous presence in circulation in health and disease [reviewed in Ref. Identified over 25 years ago [3], IL-18 functions by signaling through the IL-18 receptor (IL-18R), a functional heterodimer comprised of alpha and beta subunits [4,5,6,7]. Following ligand binding to the receptor, signaling follows a MyD88-dependent route . Among NK cells, this signaling can augment proliferation [11], heighten cytotoxicity [12, 13], and contribute to the production of IFN-γ [14, 15]
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