Invasive Surgery Impairs the Regulatory Function of Human CD56bright Natural Killer Cells in Response to Staphylococcus aureus. Suppression of Interferon-γ Synthesis

Reinhardt, Rudolf; Pohlmann, Stephanie; Kleinertz, Holger; Hepner-Schefczyk, Monika; Paul, Andreas; Flohé, Stefanie B.

doi:10.1371/journal.pone.0130155

Cited by 22 publications

(24 citation statements)

References 32 publications

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“…Next, we asked whether MSCs exert their stimulatory capacity not only under physiological conditions but also under pathological conditions that are associated with suppressed NK cell function. We have evidence that NK cells from critically ill patients after major injury and surgery are impaired in function [ 14 , 15 ]. In a small pilot study, we investigated the IFN-γ release from NK cells isolated from patients after severe injury and evaluated whether it was modulated by MSCs from healthy individuals.…”

Section: Resultsmentioning

confidence: 99%

Human mesenchymal stromal/stem cells acquire immunostimulatory capacity upon cross-talk with natural killer cells and might improve the NK cell function of immunocompromised patients

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 99%

Human mesenchymal stromal/stem cells acquire immunostimulatory capacity upon cross-talk with natural killer cells and might improve the NK cell function of immunocompromised patients

et al. 2016

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“…A review by Souza-Fonseca-Guimaraes et al (100) exposed the favorable and detrimental effects of activated NK cells on bacterialinfected cells; however, studies on the particular effect of CD56 bright cells on bacterial infections are scarce. Nevertheless, a recent investigation by Reinhardt et al (102) showed that, after invasive visceral surgery, IFN-g production by CD56…”

Section: Cd56mentioning

confidence: 99%

Human CD56bright NK Cells: An Update

Michel

Poli

Cuapio

et al. 2016

The Journal of Immunology

314

273

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Human NK cells can be subdivided into various subsets based on the relative expression of CD16 and CD56. In particular, CD56brightCD16−/dim NK cells are the focus of interest. They are considered efficient cytokine producers endowed with immunoregulatory properties, but they can also become cytotoxic upon appropriate activation. These cells were shown to play a role in different disease states, such as cancer, autoimmunity, neuroinflammation, and infection. Although their phenotype and functional properties are well known and have been extensively studied, their lineage relationship with other NK cell subsets is not fully defined, nor is their precise hematopoietic origin. In this article, we summarize recent studies about CD56bright NK cells in health and disease and briefly discuss the current controversies surrounding them.

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“…CD3 − CD56 bright CD16 neg NK cell subsets are regarded as the main cytokine producing NK cells (CD56 bright ). Reinhardt et al [ 40 ] showed that peripheral blood CD56 bright NK cells have exceptionally reduced IFNγ production when stimulated with staphylococcus aureus or recombinant IL-12 on POD1. They observed a significant decrease in IL-12R on CD56 bright NK cells, however this did not affect the pSTAT4 levels in post-operative surgery patients which is involved in the transcriptional regulation of IFNγ [ 41 ].…”

Section: Natural Killer Cell Dysfunction After Surgerymentioning

confidence: 99%

“…They observed a significant decrease in IL-12R on CD56 bright NK cells, however this did not affect the pSTAT4 levels in post-operative surgery patients which is involved in the transcriptional regulation of IFNγ [ 41 ]. Furthermore, neutralizing antibodies against IL-10 did not restore post-operative IFNγ production which, when taken together with the observation that pSTAT4 levels were not affected indicates that a cytokine-independent affliction is altering NK cell cytokine secretion [ 40 ]. Research from our lab extends these findings as we have seen an inability of NK cell stimulation from whole blood which persists for up to four weeks after surgery in CRC patients [ 42 ].…”

Section: Natural Killer Cell Dysfunction After Surgerymentioning

confidence: 99%

Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery

Angka

Khan

Kilgour

et al. 2017

IJMS

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The physiological changes that occur immediately following cancer surgeries initiate a chain of events that ultimately result in a short pro-, followed by a prolonged anti-, inflammatory period. Natural Killer (NK) cells are severely affected during this period in the recovering cancer patient. NK cells play a crucial role in anti-tumour immunity because of their innate ability to differentiate between malignant versus normal cells. Therefore, an opportunity arises in the aftermath of cancer surgery for residual cancer cells, including distant metastases, to gain a foothold in the absence of NK cell surveillance. Here, we describe the post-operative environment and how the release of sympathetic stress-related factors (e.g., cortisol, prostaglandins, catecholamines), anti-inflammatory cytokines (e.g., IL-6, TGF-β), and myeloid derived suppressor cells, mediate NK cell dysfunction. A snapshot of current and recently completed clinical trials specifically addressing NK cell dysfunction post-surgery is also discussed. In collecting and summarizing results from these different aspects of the surgical stress response, a comprehensive view of the NK cell suppressive effects of surgery is presented. Peri-operative therapies to mitigate NK cell suppression in the post-operative period could improve curative outcomes following cancer surgery.

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Invasive Surgery Impairs the Regulatory Function of Human CD56bright Natural Killer Cells in Response to Staphylococcus aureus. Suppression of Interferon-γ Synthesis

Cited by 22 publications

References 32 publications

Human mesenchymal stromal/stem cells acquire immunostimulatory capacity upon cross-talk with natural killer cells and might improve the NK cell function of immunocompromised patients

Human mesenchymal stromal/stem cells acquire immunostimulatory capacity upon cross-talk with natural killer cells and might improve the NK cell function of immunocompromised patients

Human CD56bright NK Cells: An Update

Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery

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