title: Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes.
abstract: Invading human leukocyte antigen-G+ (HLA-G+) extravillous trophoblasts (EVT) are rare cells that are believed to play a key role in the prevention of a maternal immune attack on foreign fetal tissues. Here highly purified HLA-G+ EVT and HLA-G- villous trophoblasts (VT) were isolated. Culture on fibronectin that EVT encounter on invading the uterus increased HLA-G, EGF-Receptor-2, and LIF-Receptor expression on EVT, presumably representing a further differentiation state. Microarray and functional gene set enrichment analysis revealed a striking immune-activating potential for EVT that was absent in VT. Cocultures of HLA-G+ EVT with sample matched decidual natural killer cells (dNK), macrophages, and CD4+ and CD8+ T cells were established. Interaction of EVT with CD4+ T cells resulted in increased numbers of CD4+CD25(HI)FOXP3+CD45RA+ resting regulatory T cells (Treg) and increased the expression level of the Treg-specific transcription factor FOXP3 in these cells. However, EVT did not enhance cytokine secretion in dNK, whereas stimulation of dNK with mitogens or classical natural killer targets confirmed the distinct cytokine secretion profiles of dNK and peripheral blood NK cells (pNK). EVT are specialized cells involved in maternal-fetal tolerance, the properties of which are not imitated by HLA-G-expressing surrogate cell lines.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; jlstrom@fas.harvard.edu tilburgs@fas.harvard.edu.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tilburgs
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; PhD Program in Experimental Biology and Biomedicine, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
authors.forename: Ângela C
authors.identifier: http://orcid.org/0000-0002-6731-8190
authors.initials: ÂC
authors.lastname: Crespo
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Anita
authors.initials: A
authors.lastname: van der Zwan
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Basya
authors.initials: B
authors.lastname: Rybalov
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637;
authors.forename: Barbara
authors.initials: B
authors.lastname: Stranger
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Lucy
authors.initials: L
authors.lastname: Gardner
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Ashley
authors.initials: A
authors.lastname: Moffett
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; jlstrom@fas.harvard.edu tilburgs@fas.harvard.edu.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Strominger
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D059951:HLA-G Antigens / Q000276:immunology*; D006801:Humans; D007962:Leukocytes / Q000276:immunology*; D014158:Transcription, Genetic; D014327:Trophoblasts / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D059951:HLA-G Antigens
keywords: FOXP3; NK cell; Treg; human; pregnancy