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Trimester Extravillous Cytotrophoblast Decidual NK Cells Alter in Vitro First Decidual NK Cells Alter In Vitro First Trimester Extravillous Cytotrophoblast Migration: A Role for IFN-γ This information is current as Yuxiang Hu, Jan P. Dutz, Colin D. MacCalman, Paul Yong, of September 25, 2021. Rusung Tan and Peter von Dadelszen J Immunol 2006; 177:8522-8530; ; doi: 10.4049/jimmunol.177.12.8522 http://www.jimmunol.org/content/177/12/8522 Downloaded from References This article cites 46 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/177/12/8522.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Decidual NK Cells Alter In Vitro First Trimester Extravillous Cytotrophoblast Migration: A Role for IFN-␥1 Yuxiang Hu,*¶ Jan P. Dutz,†¶ Colin D. MacCalman,*¶ Paul Yong,†§¶ Rusung Tan,‡¶ and Peter von Dadelszen2*¶ Abnormal placentation results in either inadequate (consequences: recurrent miscarriage, intrauterine growth restriction, and preeclampsia) or overzealous (consequences: placenta accreta, increta, and percreta) placentation. NK cells dominate in first trimester decidua and probably control extravillous cytotrophoblast (EVT) invasion. We examined this interaction in a novel way, using NK cells and villous explants from concordant first trimester pregnancies cocultured using a new collagen (two-dimensional) model of placentation. Decidual NK (dNK) cells exerted contact-independent inhibition of normal cytotrophoblast migration, associated with changes in the cytotrophoblast expression of metalloproteases-2 and -9, and plasminogen activator inhibitor-1. dNK cells did not affect EVT proliferation and apoptosis, and cell column formation. dNK cell effects were partially reversed by Downloaded from neutralizing Abs against IFN-␥. We provide ex vivo human evidence of a direct role for dNK in modulating EVT differentiation as they form columns and then migrate from anchoring villi. The Journal of Immunology, 2006, 177: 8522–8530. he successful and tightly regulated interaction between vasion (1, 6). Severe reduction of trophoblast cells, in combination the maternal immune system and fetal tissue is a prereq- with a strong increase of maternal lymphocytes and dNK cells, is T uisite for normal pregnancy outcomes. Insufficient acqui- found in intrauterine growth restriction (7). http://www.jimmunol.org/ escence by the maternal immune system may lead to the inade- Extravillous cytotrophoblast (EVT) express novel HLA-Ib pro- quate placentation of recurrent pregnancy loss, intrauterine growth teins, HLA-G, and HLA-E (8, 9). These molecules have special restriction, and preeclampsia (1). Overzealous fetal invasion may roles in protecting trophoblast cells from maternal immune cells, lead to morbid adherence of the placenta, placenta accreta, increta, especially dNK cells. In vitro studies have shown that the cytotoxic and percreta (2). reactivity of dNK cells against HLA-G expression target cells of 3 It has been postulated that maternal decidual NK (dNK) cells various origins was inhibited (10). HLA-E is a major ligand for the play an important role in the immune regulation of trophoblast NK inhibitory receptor CD94/NKG2A (11), which mediates inhi- invasion. There is considerable evidence to support that view (3). bition of killing of dNK cells (9). In the mouse, IL-15 was essential by guest on September 25, 2021 NK cells dominate during the early phase of gestation when pla- for the support of NK cell differentiation in the decidualizing cental trophoblast cells invade into decidua (4), and are found par- uterus (12). dNK maintained with IL-15 in vitro have no cytotox- ticularly around infiltrating trophoblast. This activity suggests a icity against trophoblast (13). This result suggests that, in normal role in regulating the degree of invasion and differentiation of the pregnancy, dNK are not cytotoxic against cytotrophoblast. trophoblast (5). Preeclampsia, and the related fetal growth restric- During implantation, cytotrophoblast leave the tips of anchoring tion, are interpreted as consequences of impaired trophoblast in- villi and become EVT. Initially, the EVT form cell columns, then invade and migrate from the columns into the maternal tissue, the ␣ ␤ † ‡ decidua. The EVT at the villus tip are 6 4 integrin positive, the *Department of Obstetrics and Gynaecology, Department of Medicine, Department ␣ ␤ of Pathology and Laboratory Medicine, and §Department of Medical Genetics, Uni- EVT in the columns are 5 1 integrin positive, and the invading versity of British Columbia, Vancouver, British Columbia, Canada; and ¶Child and ␣ ␤ EVT are 1 1 integrin positive (14, 15). Family Research Institute, Centre for Healthcare Innovation and Improvement, and Programs in Infection and Immunity and Reproductive Health, Vancouver, British A well-established experimental model of placentation involves Columbia, Canada the use of chorionic villi from first trimester terminations of preg- Received for publication March 15, 2006. Accepted for publication September nancy cultured as tissue explants on either collagen (two-dimen- 19. 2006. sional model) (16, 17) or Matrigel (three-dimensional model) (18). The costs of publication of this article were defrayed in part by the payment of page ␣ ␣ In the two-dimensional model, the integrin 1 and 5 changes of charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. invading EVT are not noted (16), whereas they are with the Ma- trigel model (18). 1 This study was funded by a Pilot Grant from the Infection and Immunity Program, Child and Family Research Institute. Y.H. is funded by grants from the Canadian IFN-␥, a cytokine secreted by both activated T lymphocytes and Institutes for Health Research, from whom P.v.D. receives salary support. C.D.M. and NK, is best known for its immunological functions. It has been P.v.D. receive salary support from the Child and Family Research Institute. P.v.D. and ␥ R.T. receive salary support from the Michael Smith Foundation for Health Research. used to treat viral infections (19, 20). However, the use of IFN- 2 Address correspondence and reprint requests to Dr. Peter von Dadelszen, Depart- in pregnancy might exert a deleterious effect, such as increased ment of Obstetrics and Gynaecology, University of British Columbia, 2H30-4500 miscarriage (21). IFN-␥ halts trophoblast migration in explant cul- Oak Street, Vancouver, British Columbia V6H 3N1, Canada. E-mail address: ture (22, 23), as does TNF-␣. Others have reported that the fol- [email protected] 3 lowing factors also contribute trophoblast migration inhibition: Abbreviations used in this paper: dNK, decidual NK; EVT, extravillous cytotro- ␤ ␤ phoblast; TIMP, tissue inhibitor of metalloprotease; MTS, 3-(4,5-dimethylthiazol-2- TGF- 1, TGF- 2, IL-10, and tissue inhibitor of metalloproteases yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; PAI, plasmino- (TIMP)-1 (17, 22, 24–29). The role of dNK in controlling EVT gen activator inhibitor; CM, dNK-derived conditioned medium; HF, hollow fiber; IQR, interquartile range; MMP, matrix metalloprotease; uPA, urokinase-type protease differentiation and invasion has not been fully determined in a activator. human model of placentation. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 8523 In this study, we have tested the hypothesis that coculturing first PAI-1 (clone MA-56A7C10; University of Leuven, Leuven, Belgium) was trimester villus explants with dNK will alter in vitro EVT migra- also tested at 10 ␮g/ml, both individually and in combination. tion. Using a new model in which dNK and villus explants were cocultured, we show that dNK cells limit trophoblast migration but Assessment of cell columns, migration, and trophoblast not proliferation, apoptosis, and differentiation. This activity is differentiation mainly through the action of soluble mediators. Using Abs to neu- EVT outgrowth and migration occurs largely across the surface of the gel tralize IFN-␥ partially reversed this effect. as described previously (32, 33). Outgrowth was examined qualitatively taking into account the size, distance, morphology of the constituent cells, and their interrelationships, including cell-cell adhesion and sheet integrity, Materials and Methods although size varied greatly among tips (Nikon Eclipse TS100-F micro- Preparation and culture of dNK cells scope). Semiquantitative evaluation of cytotrophoblast outgrowth from ex- plants was conducted by analyzing individual sites at villous tips. Images We obtained decidual tissue from healthy women undergoing elective were taken at different time points with
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