Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy.
Decidual natural killer (dNK) cells express an array of activation receptors to regulate placental immunity and development during early pregnancy. We investigated the functional character of human dNK cells during the first and second trimester of gestation and the interaction between dNK and trophoblast cells. Although the frequency of CD56+CD16-dNK among the total CD45+leukocytes did not change over this period, the expression of the activating receptors, NKp80 and NKG2D, was greatly upregulated. We observed a significantly higher number of extravillous trophoblast cells in proximity to the dNK cells in the first trimester in comparison with the second trimester decidua. NKG2D expression by first trimester dNK cells was decreased when co-cultured with the HTR-8 trophoblast cell line. In the second trimester, functional markers of dNK activation, i.e., angiogenic factor production (e.g., vascular endothelial growth factor, interleukin-8, interferon-gamma), remained stable despite an increase in NKp80 or NKG2D surface expression. Furthermore, the degranulation capacity of dNK cells, as assessed by CD107a, was decreased in the second trimester. We suggest that in the first trimester, trophoblast-dNK interactions generate a population of dNK cells with a suppressed activating phenotype. In the second trimester, the loss of trophoblast-dNK interactions led to the inhibition of dNK cell function, although their activating receptor expression was increased. We speculate that during pregnancy, two mechanisms operate to modulate the dNK cell activation:suppression of activating receptor levels in the first trimester by trophoblasts and disengagement of receptor-ligand coupling in the second trimester.
Research Centre for Women's and Infants' Health, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada.
Jianhong
J
Zhang
Research Centre for Women's and Infants' Health, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada.|Department of Obstetrics & Gynaecology, University of Toronto, Toronto, ON M5G 1L4, Canada.
Caroline E
CE
Dunk
Research Centre for Women's and Infants' Health, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada.|Department of Physiology, University of Toronto, Toronto, ON M5G 1L4, Canada.
Melissa
M
Kwan
Institute of Human Development, University of Manchester, Manchester, M13 9WL, UK.|St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
Rebecca L
RL
Jones
Institute of Human Development, University of Manchester, Manchester, M13 9WL, UK.|St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
Lynda K
LK
Harris
Department of Pathology, University of Toronto, Toronto, ON M5G 1L4, Canada.
Sarah
S
Keating
Research Centre for Women's and Infants' Health, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada.|Department of Obstetrics & Gynaecology, University of Toronto, Toronto, ON M5G 1L4, Canada.|Department of Physiology, University of Toronto, Toronto, ON M5G 1L4, Canada.
Stephen J
SJ
Lye
D002450:Cell Communication; D003656:Decidua / Q000166:cytology; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism*; D018655:Lymphocyte Count; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010641:Phenotype; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000276:immunology*; D011262:Pregnancy Trimester, Second / Q000276:immunology*; D055607:Receptors, Natural Killer Cell / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016209:Interleukin-8; C431711:KLRF1 protein, human; C527085:KLRK1 protein, human; D037181:Lectins, C-Type; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055607:Receptors, Natural Killer Cell; D042461:Vascular Endothelial Growth Factor A