title: Tissue-Specific Education of Decidual NK Cells.
abstract: During human pregnancy, fetal trophoblast cells invade the decidua and remodel maternal spiral arteries to establish adequate nutrition during gestation. Tissue NK cells in the decidua (dNK) express inhibitory NK receptors (iNKR) that recognize allogeneic HLA-C molecules on trophoblast. Where this results in excessive dNK inhibition, the risk of pre-eclampsia or growth restriction is increased. However, the role of maternal, self-HLA-C in regulating dNK responsiveness is unknown. We investigated how the expression and function of five iNKR in dNK is influenced by maternal HLA-C. In dNK isolated from women who have HLA-C alleles that carry a C2 epitope, there is decreased expression frequency of the cognate receptor, KIR2DL1. In contrast, women with HLA-C alleles bearing a C1 epitope have increased frequency of the corresponding receptor, KIR2DL3. Maternal HLA-C had no significant effect on KIR2DL1 or KIR2DL3 in peripheral blood NK cells (pbNK). This resulted in a very different KIR repertoire for dNK capable of binding C1 or C2 epitopes compared with pbNK. We also show that, although maternal KIR2DL1 binding to C2 epitope educates dNK cells to acquire functional competence, the effects of other iNKR on dNK responsiveness are quite different from those in pbNK. This provides a basis for understanding how dNK responses to allogeneic trophoblast affect the outcome of pregnancy. Our findings suggest that the mechanisms that determine the repertoire of iNKR and the effect of self-MHC on NK education may differ in tissue NK cells compared with pbNK.
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and as168@cam.ac.uk.
authors: Andrew M
authors: http://orcid.org/0000-0002-5072-7748
authors: AM
authors: Sharkey
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and.
authors: Shiqiu
authors: S
authors: Xiong
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and.
authors: Philippa R
authors: PR
authors: Kennedy
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and.
authors: Lucy
authors: L
authors: Gardner
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and.
authors: Lydia E
authors: LE
authors: Farrell
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and.
authors: Olympe
authors: O
authors: Chazara
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and.
authors: Martin A
authors: MA
authors: Ivarsson
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and.
authors: Susan E
authors: SE
authors: Hiby
authors: Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, United Kingdom.
authors: Francesco
authors: F
authors: Colucci
authors: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and.
authors: Ashley
authors: A
authors: Moffett
mesh_terms: D003656:Decidua / Q000166:cytology / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D005787:Gene Frequency / Q000235:genetics / Q000276:immunology; D005805:Genes, MHC Class I / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D011225:Pre-Eclampsia / Q000276:immunology; D011247:Pregnancy; D011256:Pregnancy Outcome; D011485:Protein Binding / Q000276:immunology; D054342:Receptors, KIR2DL1 / Q000096:biosynthesis / Q000235:genetics*; D054344:Receptors, KIR2DL3 / Q000096:biosynthesis / Q000235:genetics*; D055607:Receptors, Natural Killer Cell / Q000096:biosynthesis / Q000276:immunology*; D014327:Trophoblasts / Q000276:immunology
chemical_list: D000939:Epitopes; D015236:HLA-C Antigens; C093100:KIR2DL1 protein, human; C515078:KIR2DL3 protein, human; D054342:Receptors, KIR2DL1; D054344:Receptors, KIR2DL3; D055607:Receptors, Natural Killer Cell