title: VIP boosts regulatory T cell induction by trophoblast cells in an in vitro model of trophoblast-maternal leukocyte interaction.
abstract: Inducible regulatory T cells (Tregs) exert a timely and efficient immunosuppressive action at the critical peri-implantation stage essential for maternal tolerance to the conceptus. Vasoactive intestinal peptide (VIP) promotes anti-inflammatory and tolerogenic profiles through binding to VIP receptors on immune cells. We evaluated whether VIP produced by trophoblast cells induces Tregs during the early interaction of maternal leukocytes with trophoblast cells, thus contributing to maternal tolerance. We used an in vitro model of maternal leukocyte-trophoblast cell interaction represented by cocultures of fertile women's PBMCs with a human trophoblast cell line (Swan-71) and evaluated the effect of VIP added exogenously and of the endogenous polypeptide. VIP increased the frequency of CD4(+)CD25(+)FoxP3(+) cells after coculture, and these cells were able to suppress the maternal alloresponse. VIP also increased the frequency of CD4(+)IL10(+) and CD4(+)TGFβ(+) cells, but it did not modulate IFN-γ or IL-17 production. Swan-71 secreted VIP, and their coculture with maternal PBMCs significantly increased the frequency of Tregs. This effect was even more pronounced if the trophoblast cells had been pretreated with VIP. In both situations, the VIP antagonist prevented the increase in the frequency of CD4(+)Foxp3(+) cells, reflecting a specific effect of the polypeptide after the interaction with Swan-71 cells. Finally, the increase in CD4(+)CD25(+)FoxP3(+) frequency was prevented by an anti-TGF-β Ab and a VIP antagonist. These results suggest that VIP could have an active role in the immunoregulatory processes operating in the maternal-placental interface by contributing to the induction of Tregs through a mechanism involving TGF-β1.
authors: *Laboratory of Immunopharmacology, University of Buenos Aires School of Sciences, IQUIBICEN-CONICET (National Research Council), Buenos Aires, Argentina; Reproductive Immunology Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA; and University of Buenos Aires School of Medicine, Buenos Aires, Argentina.
authors: Laura
authors: L
authors: Fraccaroli
authors: *Laboratory of Immunopharmacology, University of Buenos Aires School of Sciences, IQUIBICEN-CONICET (National Research Council), Buenos Aires, Argentina; Reproductive Immunology Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA; and University of Buenos Aires School of Medicine, Buenos Aires, Argentina.
authors: Esteban
authors: E
authors: Grasso
authors: *Laboratory of Immunopharmacology, University of Buenos Aires School of Sciences, IQUIBICEN-CONICET (National Research Council), Buenos Aires, Argentina; Reproductive Immunology Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA; and University of Buenos Aires School of Medicine, Buenos Aires, Argentina.
authors: Vanesa
authors: V
authors: Hauk
authors: *Laboratory of Immunopharmacology, University of Buenos Aires School of Sciences, IQUIBICEN-CONICET (National Research Council), Buenos Aires, Argentina; Reproductive Immunology Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA; and University of Buenos Aires School of Medicine, Buenos Aires, Argentina.
authors: Daniel
authors: D
authors: Paparini
authors: *Laboratory of Immunopharmacology, University of Buenos Aires School of Sciences, IQUIBICEN-CONICET (National Research Council), Buenos Aires, Argentina; Reproductive Immunology Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA; and University of Buenos Aires School of Medicine, Buenos Aires, Argentina.
authors: Elizabeth
authors: E
authors: Soczewski
authors: *Laboratory of Immunopharmacology, University of Buenos Aires School of Sciences, IQUIBICEN-CONICET (National Research Council), Buenos Aires, Argentina; Reproductive Immunology Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA; and University of Buenos Aires School of Medicine, Buenos Aires, Argentina.
authors: Gil
authors: G
authors: Mor
authors: *Laboratory of Immunopharmacology, University of Buenos Aires School of Sciences, IQUIBICEN-CONICET (National Research Council), Buenos Aires, Argentina; Reproductive Immunology Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA; and University of Buenos Aires School of Medicine, Buenos Aires, Argentina.
authors: Claudia
authors: C
authors: Pérez Leirós
authors: *Laboratory of Immunopharmacology, University of Buenos Aires School of Sciences, IQUIBICEN-CONICET (National Research Council), Buenos Aires, Argentina; Reproductive Immunology Unit, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA; and University of Buenos Aires School of Medicine, Buenos Aires, Argentina rramhorst@qb.fcen.uba.ar.
authors: Rosanna
authors: R
authors: Ramhorst
mesh_terms: D002450:Cell Communication; D002460:Cell Line; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
chemical_list: D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D014660:Vasoactive Intestinal Peptide
keywords: TGF-β; early pregnancy; iTreg; tolerance