title: Ly49 receptors activate angiogenic mouse DBA⁺ uterine natural killer cells.
abstract: In humans, specific patterns of killer immunoglobulin-like receptors (KIRs) expressed by uterine natural killer (uNK) cells are linked through HLA-C with pregnancy complications (infertility, recurrent spontaneous abortion, intrauterine growth restriction and preeclampsia). To identify mechanisms underpinning the associations between NK cell activation and pregnancy success, pregnancies were studied in mice with genetic knockdown (KD) of the MHC-activated Ly49 receptor gene family. B6.Ly49(KD) pregnancies were compared to normal control B6.Ly49(129) and C57BL/6 (B6) pregnancies. At mid-pregnancy (gestation day (gd9.5)), overall uNK cell (TCRβ(-)CD122(+)DBA(+)DX5(-) (DBA(+)DX5(-))) and TCRβ(-)CD122(+)DBA(-)DX5(+) (DBA(-)DX5(+))) frequencies in pregnant uterus were similar between genotypes. Ly49(KD) lowered the normal frequencies of Ly49(+) uNK cells from 90.3% to 47.8% in DBA(-)DX5(+) and 78.8% to 6.3% in DBA(+)DX5(-) uNK cell subtypes. B6.Ly49(KD) matings frequently resulted in expanded blastocysts that did not implant (subfertility). B6.Ly49(KD) mice that established pregnancy had gestational lengths and litter sizes similar to controls. B6.Ly49(KD) neonates, however, were heavier than controls. B6.Ly49(KD) implantation sites lagged in early (gd6.5) decidual angiogenesis and were deficient in mid-pregnancy (gd10.5) spiral arterial remodelling. Ultrastructural analyses revealed that B6.Ly49(KD) uNK cells had impaired granulogenesis, while immunocytochemistry revealed deficient vascular endothelial cell growth factor (VEGFA) production. Perforin and IFNG expression were normal in B6.Ly49(KD) uNK cells. Thus, in normal mouse pregnancies, Ly49 receptor signaling must promote implantation, early decidual angiogenesis and mid-pregnancy vascular remodelling. Disturbances in these functions may underlie the reported genetic associations between human pregnancy complications and the inability of specific conceptus MHCs to engage activating KIR on uNK cells.
authors: 1] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada [2] Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
authors: Patricia D A
authors: PD
authors: Lima
authors: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors: Megan M
authors: MM
authors: Tu
authors: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors: Mir Munir A
authors: MM
authors: Rahim
authors: 1] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada [2] Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
authors: Annie R
authors: AR
authors: Peng
authors: Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
authors: B Anne
authors: BA
authors: Croy
authors: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors: Andrew P
authors: AP
authors: Makrigiannis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D010064:Embryo Implantation / Q000235:genetics; D005260:Female; D015236:HLA-C Antigens / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics; D011247:Pregnancy; D012269:Ribosomal Proteins / Q000378:metabolism; D015398:Signal Transduction; D014599:Uterus / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling / Q000235:genetics
chemical_list: D015236:HLA-C Antigens; D055650:NK Cell Lectin-Like Receptor Subfamily A; D012269:Ribosomal Proteins; D042461:Vascular Endothelial Growth Factor A; C040343:ribosomal protein S19; C467480:vascular endothelial growth factor A, mouse