title: Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function.
abstract: During mammalian pregnancy maternal-fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. Exosomes are membrane nanovesicles with defined morphology, which are secreted from endosomal multivesicular bodies (MVB) upon fusion with the plasma membrane. Previously, we reported that the MHC class I chain-related (MIC) proteins A and B, human ligands of the activating NK cell receptor NKG2D, are expressed by placenta, sorted to MVB of syncytiotrophoblast and probably released via MIC-bearing exosomes. In this report, we show that the second family of human NKG2D ligands, the UL-16 binding proteins (ULBP), is also expressed by placenta. Importantly, this expression was not due to placental CMV infection. Immunoelectron microscopy disclosed that ULBP1-5 are produced and retained in MVB of the syncytiotrophoblast on microvesicles/exosomes. Using human placenta explant cultures and different assays, we demonstrate that exosomes bearing NKG2D ligands are released by human placenta. Isolated placental exosomes carried ULBP1-5 and MIC on their surface and induced down-regulation of the NKG2D receptor on NK, CD8(+), and gammadelta T cells, leading to reduction of their in vitro cytotoxicity without affecting the perforin-mediated lytic pathway. Release of placental NKG2D ligands via exosomes is an alternative mechanism for generation of bioactive soluble form of these ligands. These findings highlight a role for NKG2D ligand-bearing placental exosomes in the fetal immune escape and support the view of placenta as a unique immunosuppressive organ.
authors: Department of Clinical Immunology, Umeå University, Sweden.
authors: Malin
authors: M
authors: Hedlund
authors: Ann-Christin
authors: AC
authors: Stenqvist
authors: Olga
authors: O
authors: Nagaeva
authors: Lennart
authors: L
authors: Kjellberg
authors: Marianne
authors: M
authors: Wulff
authors: Vladimir
authors: V
authors: Baranov
authors: Lucia
authors: L
authors: Mincheva-Nilsson
mesh_terms: D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D011992:Endosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055354:Exosomes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007165:Immunosuppression Therapy; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009924:Organ Culture Techniques; D010920:Placenta / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011257:Pregnancy Proteins; C423230:ULBP2 protein, human