title: Update on pathways regulating the activation of uterine Natural Killer cells, their interactions with decidual spiral arteries and homing of their precursors to the uterus.
abstract: Virgin adult C57Bl/6J mouse uterus contains a population of small, non-granulated Natural Killer (NK) cells with balanced expression of NK cell activating and inhibiting LY49 receptors. Coincident with blastocyst implantation and decidualization, uterine (u)NK cells become activated. The surface glycoslyation of uNK changes, the cells proliferate and they induce production of interferon (IFN)gamma, perforin, serine esterases and other molecules, including angiogenic factors. Mouse strains genetically ablated in uNK cells fail to undergo modification of spiral artery segments that branch from the uterine artery and feed into the placenta and these mice do not sustain a robust decidualization response. IFN-gamma is thought, from bone marrow transplantation and therapeutic studies, to be the key uNK-cell derived mediator regulating gene expression in vascular and decidual tissues. Here, we review recent studies showing that IL-15 is the critical cytokine controlling uNK cell differentiation and that uNK cells are activated by either IL-12 or IL-18 and by other factors when both IL-12 and IL-18 are genetically absent from implantation sites. We address possible roles of the IFN-gamma regulated gene alpha2-macroglobulin (alpha2-M) in regulation of the position of fetal trophoblast within the walls of the spiral arteries, and we discuss approaches that have been successful in evaluating mechanisms involved in homing of mouse uNK cell precursors to the uterus. These approaches maybe applicable to studies in women. Our studies show that complex immuno-physiological events contribute to spiral artery modification by mid-gestation in mice.
authors.affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Ont. N1G 2W1, Guelph, Canada. acroy@uoguelph.ca
authors.forename: B Anne
authors.initials: BA
authors.lastname: Croy
authors.forename: Souad
authors.initials: S
authors.lastname: Esadeg
authors.forename: Sirirak
authors.initials: S
authors.lastname: Chantakru
authors.forename: Marianne
authors.initials: M
authors.lastname: van den Heuvel
authors.forename: Valdemar A
authors.initials: VA
authors.lastname: Paffaro
authors.forename: Hong
authors.initials: H
authors.lastname: He
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Black
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kiso
authors.forename: Jianhong
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D001158:Arteries / Q000502:physiology; D003656:Decidua / Q000098:blood supply*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D055630:Receptors, NK Cell Lectin-Like; D014327:Trophoblasts / Q000502:physiology; D014599:Uterus / Q000166:cytology / Q000276:immunology*; D000511:alpha-Macroglobulins / Q000235:genetics / Q000502:physiology
chemical_list: D000950:Antigens, Ly; D007378:Interleukins; D037181:Lectins, C-Type; D055630:Receptors, NK Cell Lectin-Like; D000511:alpha-Macroglobulins; D007371:Interferon-gamma