title: 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.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  Human 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.
  
  
  RESULTS
  In 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. CD56(bright) NK cells expressed higher levels of CCR2 and were more sensitive to CCL2-mediated priming by MSCs and by recombinant CCR2 ligands than cytotoxic CD56(dim) 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.
  
  
  CONCLUSIONS
  A 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.
authors.affiliation: Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 171, D-45147, Essen, Germany.
authors.forename: Rongtao
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 171, D-45147, Essen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Rekasi
authors.affiliation: Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 171, D-45147, Essen, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Hepner-Schefczyk
authors.affiliation: Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 171, D-45147, Essen, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Fessmann
authors.affiliation: Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Petri
authors.affiliation: Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bruderek
authors.affiliation: Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Brandau
authors.affiliation: Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 171, D-45147, Essen, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Jäger
authors.affiliation: Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 171, D-45147, Essen, Germany. stefanie.flohe@uk-essen.de.
authors.forename: Stefanie B
authors.initials: SB
authors.lastname: Flohé
mesh_terms: D000328:Adult; D000906:Antibodies / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D056747:Immunomodulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008875:Middle Aged; D009104:Multiple Trauma / Q000276:immunology* / Q000473:pathology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology; D015599:Trauma Severity Indices; D000096743:Interferon gamma Receptor
chemical_list: D000906:Antibodies; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D007371:Interferon-gamma; D018664:Interleukin-12; D020382:Interleukin-18; D054390:Receptors, CCR2; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C111835:CCL2 protein, human; C515334:CCR2 protein, human; C000589760:IL18 protein, human
keywords: CCL2; CCR2; Chemokines; Immunosuppression; Injury; Interferon gamma; MCP-1; Mesenchymal stem cells; Mesenchymal stromal cells; Natural killer cells; Trauma