Abstract
BackgroundThe suppressive effect of mesenchymal stromal/stem cells (MSCs) on diverse immune cells is well known, but it is unclear whether MSCs additionally possess immunostimulatory properties. We investigated the impact of human MSCs on the responsiveness of primary natural killer (NK) cells in terms of cytokine secretion.MethodsHuman MSCs were generated from bone marrow and nasal mucosa. NK cells were isolated from peripheral blood of healthy volunteers or of immunocompromised patients after severe injury. NK cells were cultured with MSCs or with MSC-derived conditioned media in the absence or presence of IL-12 and IL-18. C-C chemokine receptor (CCR) 2, C-C chemokine ligand (CCL) 2, and the interferon (IFN)-γ receptor was blocked by specific inhibitors or antibodies. The synthesis of IFN-γ and CCL2 was determined.ResultsIn the absence of exogenous cytokines, trace amounts of NK cell-derived IFN-γ licensed MSCs for enhanced synthesis of CCL2. In turn, MSCs primed NK cells for increased release of IFN-γ in response to IL-12 and IL-18. Priming of NK cells by MSCs occurred in a cell–cell contact-independent manner and was impaired by inhibition of the CCR2, the receptor of CCL2, on NK cells. CD56bright NK cells expressed higher levels of CCR2 and were more sensitive to CCL2-mediated priming by MSCs and by recombinant CCR2 ligands than cytotoxic CD56dim NK cells. NK cells from severely injured patients were impaired in cytokine-induced IFN-γ synthesis. Co-culture with MSCs or with conditioned media from MSCs and MSC/NK cell co-cultures from healthy donors improved the IFN-γ production of the patients’ NK cells in a CCR2-dependent manner.ConclusionsA positive feedback loop driven by NK cell-derived IFN-γ and MSC-derived CCL2 increases the inflammatory response of cytokine-stimulated NK cells not only from healthy donors but also from immunocompromised patients. Therapeutic application of MSCs or their soluble factors might thus improve the NK function after severe injury.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0353-9) contains supplementary material, which is available to authorized users.
Highlights
The suppressive effect of mesenchymal stromal/stem cells (MSCs) on diverse immune cells is well known, but it is unclear whether MSCs possess immunostimulatory properties
Because contact with MSCs during stimulation of natural killer (NK) cells with IL-12 and IL-18 was not required to increase the release of IFN-γ, we investigated whether soluble factor(s) derived from MSCs were responsible for the priming effect on NK cells
MSCs prime NK cells for increased IFN-γ secretion We have previously shown that human bone marrowderived MSCs prime NK-92 cells, a human NK cell line, for increased release of IFN-γ upon stimulation with IL12 and IL-18
Summary
The suppressive effect of mesenchymal stromal/stem cells (MSCs) on diverse immune cells is well known, but it is unclear whether MSCs possess immunostimulatory properties. MSCs are defined according to their lack of the hematopoietic and endothelial markers CD45 and CD34 and their expression of the stromal markers CD105, CD90, CD29, and CD73 [1]. MSCs inhibit the proliferation of T cells, the release of inflammatory cytokines by dendritic cells and macrophages, the proliferation and immunoglobulin production of B cells, and the cytotoxic activity of natural killer (NK) cells [6]. This regulatory activity of MSCs has led to the development of novel therapeutic approaches in the treatment of inflammatory disorders such as graft-versus-host disease or autoimmunity. More recently it has been shown that MSCs do not act as immunosuppressant cells by “default” but may enhance inflammation depending on the microenvironment [7]
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