Activating KIR2DS4 Is Expressed by Uterine NK Cells and Contributes to Successful Pregnancy.
Tissue-specific NK cells are abundant in the pregnant uterus and interact with invading placental trophoblast cells that transform the maternal arteries to increase the fetoplacental blood supply. Genetic case-control studies have implicated killer cell Ig-like receptor (KIR) genes and their HLA ligands in pregnancy disorders characterized by failure of trophoblast arterial transformation. Activating KIR2DS1 or KIR2DS5 (when located in the centromeric region as in Africans) lower the risk of disorders when there is a fetal HLA-C allele carrying a C2 epitope. In this study, we investigated another activating KIR, KIR2DS4, and provide genetic evidence for a similar effect when carried with KIR2DS1 KIR2DS4 is expressed by ∼45% of uterine NK (uNK) cells. Similarly to KIR2DS1, triggering of KIR2DS4 on uNK cells led to secretion of GM-CSF and other chemokines, known to promote placental trophoblast invasion. Additionally, XCL1 and CCL1, identified in a screen of 120 different cytokines, were consistently secreted upon activation of KIR2DS4 on uNK cells. Inhibitory KIR2DL5A, carried in linkage disequilibrium with KIR2DS1, is expressed by peripheral blood NK cells but not by uNK cells, highlighting the unique phenotype of uNK cells compared with peripheral blood NK cells. That KIR2DS4, KIR2DS1, and some alleles of KIR2DS5 contribute to successful pregnancy suggests that activation of uNK cells by KIR binding to HLA-C is a generic mechanism promoting trophoblast invasion into the decidua.
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; philippa.kennedy@manchester.ac.uk am485@cam.ac.uk.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.|Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, United Kingdom.
Philippa R
0000-0003-0239-5440
PR
Kennedy
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.
Olympe
0000-0003-0480-7808
O
Chazara
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.
Lucy
0000-0003-1735-2005
L
Gardner
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.
Martin A
0000-0002-7745-1331
MA
Ivarsson
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.
Lydia E
0000-0002-7643-6009
LE
Farrell
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.|Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, United Kingdom; and.
Shiqiu
0000-0003-4056-8779
S
Xiong
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.
Susan E
SE
Hiby
Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.|Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0SP, United Kingdom.
Francesco
0000-0001-5193-6376
F
Colucci
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.
Andrew M
0000-0002-5072-7748
AM
Sharkey
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; philippa.kennedy@manchester.ac.uk am485@cam.ac.uk.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.
Ashley
0000-0002-8388-9073
A
Moffett
D002460:Cell Line; D003656:Decidua / Q000166:cytology / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D011247:Pregnancy / Q000276:immunology*; D054340:Receptors, KIR / Q000276:immunology*; D014327:Trophoblasts / Q000166:cytology / Q000276:immunology*
C496212:KIR2DS1 protein, human; C473953:KIR2DS4 protein, human; C531595:KIR2DS5 protein, human; D054340:Receptors, KIR; D016178:Granulocyte-Macrophage Colony-Stimulating Factor