title: Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy.
abstract: The dominant lymphocytes in human and murine implantation sites are transient, pregnancy-associated uterine natural killer (uNK) cells. These cells are a major source of interferon (IFN)-gamma. Implantation sites in mice lacking uNK cells (alymphoid recombinase activating gene [RAG]-2(-/)- common cytokine receptor chain gamma [gamma(c)](-/)-) or IFN-gamma signaling (IFN-gamma(-/)- or IFN-gammaRalpha(-/)-) fail to initiate normal pregnancy-induced modification of decidual arteries and display hypocellularity or necrosis of decidua. To investigate the functions of uNK cell-derived IFN-gamma during pregnancy, RAG-2(-/)-gamma(c)(-/)- females were engrafted with bone marrow from IFN-gamma(-/)- mice, IFN-gamma signal-disrupted mice (IFN-gammaRalpha(-/)- or signal transducer and activator of transcription [Stat]-1(-/)-), or from mice able to establish normal uNK cells (severe combined immunodeficient [SCID] or C57BL/6). Mated recipients were analyzed at midgestation. All grafts established uNK cells. Grafts from IFN-gamma(-/)- mice did not reverse host vascular or decidual pathology. Grafts from all other donors promoted modification of decidual arteries and decidual cellularity. Grafts from IFN-gammaRalpha(-/)- or Stat-1(-/)- mice overproduced uNK cells, all of which were immature. Grafts from IFN-gamma(-/)-, SCID, or C57BL/6 mice produced normal, mature uNK cells. Administration of murine recombinant IFN-gamma to pregnant RAG-2(-/)-gamma(c)(-/)- mice initiated decidual vessel modification and promoted decidual cellularity in the absence of uNK cells. These in vivo findings strongly suggest that uNK cell-derived IFN-gamma modifies the expression of genes in the uterine vasculature and stroma, which initiates vessel instability and facilitates pregnancy-induced remodeling of decidual arteries.
authors.affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1. aashkar@uoguelph.ca
authors.forename: A A
authors.initials: AA
authors.lastname: Ashkar
authors.forename: J P
authors.initials: JP
authors.lastname: Di Santo
authors.forename: B A
authors.initials: BA
authors.lastname: Croy
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D003656:Decidua / Q000502:physiology*; D005260:Female; D007371:Interferon-gamma / Q000502:physiology*; D007694:Killer Cells, Natural / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014599:Uterus / Q000098:blood supply* / Q000276:immunology
chemical_list: D015703:Antigens, CD; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C064655:V(D)J recombination activating protein 2; D007371:Interferon-gamma