title: Platelet-Derived Ectosomes Reduce NK Cell Function.
abstract: Platelet (PLT) transfusions are potentially life saving for individuals with low PLT numbers; however, previous work revealed that PLT transfusions are associated with increased infection risk. During storage, PLT intended for transfusion continuously shed ectosomes (Ecto) from their surface, which express immunomodulatory molecules like phosphatidylserine or TGF-β1. Recently, PLT-Ecto were shown to reduce proinflammatory cytokine release by macrophages and to favor the differentiation of naive T cells toward regulatory T cells. Whether PLT-Ecto modify NK cells remains unclear. We exposed purified NK cells and full PBMCs from healthy donors to PLT-Ecto. We found a reduced expression of several activating surface receptors (NKG2D, NKp30, and DNAM-1) and decreased NK cell function, as measured by CD107a expression and IFN-γ production. Pretreatment of PLT-Ecto with anti-TGF-β1 neutralizing Ab restored surface receptor expression and NK cell function. We further observed a TGF-β1-mediated upregulation of miR-183, which, in turn, reduced DAP12, an important protein for stabilization and downstream signaling of several activating NK cell receptors. Again, these effects could antagonized, in part, when PLT-Ecto were preincubated with anti-TGF-β1 Ab. Erythrocyte Ecto did not affect NK cells. Polymorphonuclear cell Ecto expressed MHC class I and inhibited NK cell function. In addition, they induced the secretion of TGF-β1 by NK cells, which participated in an auto/paracrine manner in the suppressive activity of polymorphonuclear cell-derived Ecto. In sum, our study showed that PLT-Ecto could inhibit NK cell effector function in a TGF-β1-dependent manner, suggesting that recipients of PLT transfusions may experience reduced NK cell function.
authors.affiliation: Immunonephrology, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland; salima.sadallah@chuv.ch.
authors.forename: Salima
authors.initials: S
authors.lastname: Sadallah
authors.affiliation: Immunotherapy Laboratories, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland; and.
authors.forename: Laurent
authors.identifier: 0000-0002-3303-881X
authors.initials: L
authors.lastname: Schmied
authors.affiliation: Immunonephrology, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland;
authors.forename: Ceylan
authors.initials: C
authors.lastname: Eken
authors.affiliation: Immunotherapy Laboratories, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland; and.
authors.forename: Hojjatollah Nozad
authors.identifier: 0000-0003-4883-9924
authors.initials: HN
authors.lastname: Charoudeh
authors.affiliation: Institute of Surgical Research, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Francesca
authors.identifier: 0000-0003-4032-3034
authors.initials: F
authors.lastname: Amicarella
authors.affiliation: Immunonephrology, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland;
authors.forename: Jürg A
authors.initials: JA
authors.lastname: Schifferli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D001792:Blood Platelets / Q000737:chemistry* / Q000502:physiology; D055252:Cell-Derived Microparticles / Q000276:immunology* / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000235:genetics; D005805:Genes, MHC Class I; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000235:genetics; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics; D035683:MicroRNAs / Q000187:drug effects / Q000235:genetics; D009000:Monocytes / Q000187:drug effects; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics; D009504:Neutrophils / Q000737:chemistry; D010718:Phosphatidylserines / Q000235:genetics; D055607:Receptors, Natural Killer Cell / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D052118:Lysosomal-Associated Membrane Protein 1; C533449:MIRN183 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C431710:NCR3 protein, human; D055628:Natural Cytotoxicity Triggering Receptor 3; D010718:Phosphatidylserines; D055607:Receptors, Natural Killer Cell; C110546:TYROBP protein, human; D016212:Transforming Growth Factor beta; C423230:ULBP2 protein, human; D007371:Interferon-gamma