Monocyte-Derived Signals Activate Human Natural Killer Cells in Response to Leishmania Parasites

Abstract

Activated natural killer (NK) cells release interferon (IFN)-γ, which is crucial for the control of intracellular pathogens such as Leishmania. In contrast to experimental murine leishmaniasis, the human NK cell response to Leishmania is still poorly characterized. Here, we investigated the interaction of human blood NK cells with promastigotes of different Leishmania species (Leishmania major, Leishmania mexicana, Leishmania infantum, and Leishmania donovani). When peripheral blood mononuclear cells or purified NK cells and monocytes (all derived from healthy blood donors from Germany without a history of leishmaniasis) were exposed to promastigotes, NK cells showed increased surface expression of the activation marker CD69. The extent of this effect varied depending on the Leishmania species; differences between dermotropic and viscerotropic L. infantum strains were not observed. Upregulation of CD69 required direct contact between monocytes and Leishmania and was partly inhibitable by anti-interleukin (IL)-18. Unexpectedly, IL-18 was undetectable in most of the supernatants (SNs) of monocyte/parasite cocultures. Confocal fluorescence microscopy of non-permeabilized cells revealed that Leishmania-infected monocytes trans-presented IL-18 to NK cells. Native, but not heat-treated SNs of monocyte/Leishmania cocultures also induced CD69 on NK cells, indicating the involvement of a soluble heat-labile factor other than IL-18. A role for the NK cell-activating cytokines IL-1β, IL-2, IL-12, IL-15, IL-21, and IFN-α/β was excluded. The increase of CD69 was not paralleled by NK cell IFN-γ production or enhanced cytotoxicity. However, prior exposure of NK cells to Leishmania parasites synergistically increased their IFN-γ release in response to IL-12, which was dependent on endogenous IL-18. CD1c+ dendritic cells were identified as possible source of Leishmania-induced IL-12. Finally, we observed that direct contact between Leishmania and NK cells reduced the expression of CD56 mRNA and protein on NK cells. We conclude that Leishmania activate NK cells via trans-presentation of IL-18 by monocytes and by a monocyte-derived soluble factor. IL-12 is needed to elicit the IFN-γ-response of NK cells, which is likely to be an important component of the innate control of the parasite.

Aspergillus�fumigatus enhances human NK cell activity by regulating M1 macrophage polarization

“…Intrahepatic macrophages reduce inflammatory injury and serve an antiviral role in the liver by interacting with NK cells (34). Monocytes regulate the functions of other cells by secreting a variety of cytokines and expressing various surface proteins (10). The interaction between NK cells and monocytes is present in various tissues and organs, and peripheral blood (35); however, to the best of our knowledge, there has been limited investigation into the interaction between NK cells and monocytes in fungal infection.…”

“…Together, natural killer cells (NK cells) and macrophages build the first immune defence line in the body for the removal of invasive microbes (10,11). The activation or inhibition of NK cells is mainly regulated by the expression of activating or inhibitory receptors on the cell surface ( 12) .…”

The priming role of dendritic cells on the cancer cytotoxic effects of cytokine-induced killer cells

“…Control of IFN-γ induction before supplementation with IL-2 and anti-CD3 antibody is crucial in creating cytotoxicity 81 . Specifically, IFN-γ activates monocytes to provide an important signal in CD56+ T-cell proliferation 82 . The addition of IL-2 and anti-CD3 then mainly provide mitotic signals 83 .…”

Role of Alarmins in the Pathogenesis of Systemic Sclerosis

“…A profibrogenetic role of IL-33 has been demonstrated for pulmonary fibrosis (idiopathic and SSc-related fibrosis), liver fibrosis (cirrhosis, viral hepatitis, primary biliary cirrhosis, and NASH), pancreatic fibrosis, intestine fibrosis (IBD), renal fibrosis, and skin fibrosis. In regard to skin fibrosis, it has been documented that the IL-33/ST2 axis associates with fibroblast proliferation, differentiation of endothelial cells, increased angiogenesis, and ECM deposition [ 106 ].…”