title: Umbilical cord blood plasma contains soluble NKG2D ligands that mediate loss of natural killer cell function and cytotoxicity.
abstract: NK cells play a key role in innate elimination of virally infected or neoplastic cells but they can be circumvented by immunoevasive mechanisms enabling viral spread or tumor progression. Engagement of the NKG2D activating receptor with soluble forms of its ligand is one such mechanism of inducing NK cell hyporesponsiveness. Interestingly, this immunoevasive strategy among others is described at the maternal-fetal interface where tolerance of the semi-allogeneic fetus is required to allow successful human pregnancy. Understanding of maternal-fetal tolerance is increasing but mechanisms preventing alloreactivity of fetal immune cells against the maternal host are less well understood. The study of umbilical cord blood has enabled insight of the fetal immune system, which appears immature and inert. We have found that soluble NKG2D ligands (sNKG2DLs) are present in cord blood plasma (CBP) and associate with adult NK cell hyporesponsiveness demonstrated by reduced CD107a expression and secretion of IFN-γ upon stimulation. The capacity of NK cells to kill K562 cells or proliferate was also reduced by incubation with CBP; however, physical removal of sNKG2DL from CBP restored K562 lytic function and NKG2D expression. Therefore, our results strongly suggest sNKG2DLs are expressed in CBP as a mechanism of fetal-maternal tolerance in human pregnancy.
authors.affiliation: The Anthony Nolan Research Institute, The Royal Free Hospital, Hampstead, London, UK.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Cox
authors.affiliation: The Anthony Nolan Research Institute, The Royal Free Hospital, Hampstead, London, UK.
authors.forename: Raquel
authors.initials: R
authors.lastname: Laza-Briviesca
authors.affiliation: The Anthony Nolan Research Institute, The Royal Free Hospital, Hampstead, London, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Pearson
authors.affiliation: Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Fundación Progreso y Salud, Seville, Spain.|Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Bernat
authors.initials: B
authors.lastname: Soria
authors.affiliation: Cell Therapy Centre, Nottingham Trent University, Nottingham, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gibson
authors.affiliation: Cell Therapy Centre, Nottingham Trent University, Nottingham, UK.
authors.forename: Susana
authors.initials: S
authors.lastname: Gomez
authors.affiliation: The Anthony Nolan Research Institute, The Royal Free Hospital, Hampstead, London, UK.|Cell Therapy Centre, Nottingham Trent University, Nottingham, UK.|UCL Cancer Institute, Royal Free Campus, London, UK.
authors.forename: J Alejandro
authors.initials: JA
authors.lastname: Madrigal
authors.affiliation: The Anthony Nolan Research Institute, The Royal Free Hospital, Hampstead, London, UK.|UCL Cancer Institute, Royal Free Campus, London, UK.
authors.forename: Aurore
authors.initials: A
authors.lastname: Saudemont
mesh_terms: D000328:Adult; D005260:Female; D005312:Fetal Blood / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000097:blood / Q000276:immunology; D011247:Pregnancy
chemical_list: C573415:IFNG protein, human; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; D055655:NK Cell Lectin-Like Receptor Subfamily K; D007371:Interferon-gamma
keywords: Ligand; NK cell; NKG2D; Pregnancy; Tolerance