IL‐18, but not IL‐15, contributes to the IL‐12‐dependent induction of NK‐cell effector functions by Leishmania infantum in vivo

Abstract

Activation of NK cells is a hallmark of infections with intracellular pathogens. We previously showed that the protozoan parasite Leishmania infantum triggered a rapid NK-cell response in mice that required TLR9-positive myeloid DC and IL-12, but no IFN-α/β. Here, we investigated whether IL-15 or IL-18 mediate the activity of IL-12 or function as independent activators of NK cells. In contrast to earlier studies that described IL-15 as crucial for NK-cell priming in response to TLR ligands, the expression of IFN-γ, FasL, perforin and granzyme B by NK cells in L. infantum-infected mice was completely preserved in the absence of IL-15, whereas the proliferative capacity of NK cells was lower than in WT mice. IFN-γ secretion, cytotoxicity and FasL expression of NK cells from infected IL-18−/− mice were significantly reduced compared with controls, but, unlike IL-12, IL-18 was not essential for NK-cell effector functions. Part of the NK-cell-stimulatory effect of IL-12 was dependent on IL-18. We conclude that IL-15 is not functioning as a universal NK-cell priming signal and that IL-18 contributes to the NK-cell response in visceral leishmaniasis. The cytokine requirements for NK-cell activation appear to differ contingent upon the infectious pathogen.

Leishmania-Infected Macrophages Are Targets of NK Cell-Derived Cytokines but Not of NK Cell Cytotoxicity

“…Second, NK cells and myeloid cells frequently colocalize during cutaneous or visceral leishmaniasis (3,72), raising the possibility of functional interactions. Third, previous experiments involving activation, depletion, or transfer of NK cells provided evidence for a protective role of NK cells in cutaneous and visceral leishmaniasis (3,17,24,28,34,36,39,43,(56)(57)(58)61).…”

“…We therefore cocultured L. infantum-infected BM-M with highly purified NK cells from naïve mice in the presence of IL-12 and IL-18, which are required for optimal NK cell activation in mouse cutaneous and visceral leishmaniasis (24,39,61). After 72 h of coculture, the total parasite load decreased by 76% to 97% (Fig.…”

“…A series of findings argues for a protective role of NK cells in murine leishmaniasis, at least during the early phase of infection. These include (i) the aggravated course of Leishmania infections in NK cell-deficient bg/bg (beige) mice (28) or in NK cell-depleted mice (34,36,57), (ii) the disease-ameliorating effect of the activation or transfer of NK cells in Leishmania-infected mice (34,43,56), (iii) the expression of IFN-␥ by NK cells early after infection in vivo (3,17,24,39,57,58,61), and (iv) the involvement of NK cells in the protection elicited by dendritic cell (DC)-based vaccines (54). However, it should be noted that the NK cell depletions were performed only transiently prior to and early during infection using reagents (e.g., anti-NK1.1 antibody) that were not entirely selective for NK cells.…”

“…The key players are (i) interleukin-12 (IL-12), which is essential for NK cell activation (58) and released by myeloid DCs in response to Leishmania in a Toll-like receptor 9 (TLR9)-and vascular cell adhesion molecule-1/very late antigen-4-dependent manner in vitro and in vivo (22,39,61,65); (ii) IFN-␣/␤, which accounts for the early expression of iNOS and thereby facilitates IL-12 responsiveness in L. major-infected mice (17,18); (iii) IL-18, which supports NK cell activation in L. infantum-infected mice (24); and (iv) antigen-primed CD4 ϩ T cells that activate NK cells via IL-2 in the L. major mouse model (4,57). In situ, NK cells form part of the early inflammatory infiltrate after Leishmania infection at the site of infection and colocalize with myeloid cells in vivo (3,72).…”

The Ectromelia Virus SPI-2 Protein Causes Lethal Mousepox by Preventing NK Cell Responses

“…Caspase 1 converts IL-18 and IL-1␤ from their inactive precursors to the biologically active cytokines (10). IL-18 is an inducer of IFN-␥ and a stimulator of NK cell activation and cytotoxicity (16,19,20,40,52). The SPI-2 inhibition of caspase 1 in, for instance, infected macrophages or dendritic cells (DC) might deprive developing NK cells of an environment containing IL-18, which could lead to reduced production of IFN-␥, a cytokine that is important for recovery from mousepox (23), or to reduced NK cell cytotoxicity (16).…”