The Triangle of Pregnancy Success – Decoding the Network between Regulatory T Cells, Dendritic Cells and Human Chorionic Gonadotropin in Embryo Implantation

• Applicant: Privatdozentin Dr. Anne Schumacher
• Subject Area: Reproductive Medicine, Urology ; Gynaecology and Obstetrics
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422013072

• Final Report Year: 2023

Final Report Abstract

Embryo implantation is an intimidate dialogue between maternal embryonic tissue and requires a sequence of orchestrated events to ensure successful pregnancy progression. This dialogue is promoted by molecules that are expressed by the maternal endometrium and the fetal trophoblast as well as by surrounding immune cells. However, the mechanistic pathways linking the actions of endometrial, trophoblast and immune cells are not well understood. In our research project we aimed to decipher the impact of dendritic cells (DC) and regulatory T cells (Treg) on trophoblast viability, adhesion, proliferation, migration and invasion, and to identify molecules involved in immune cell-mediated modulation of endometrial and trophoblast cells. As a subordinated goal we studied the influence of the trophoblast-derived hormone human chorionic gonadotropin (hCG) on both immune cell types with regard to embryo implantation. By applying different in vitro human heterologous implantation assays we observed that Treg and DC supported trophoblast adhesion to endometrial cells, which in the case of DC might be at least partially realized through upregulation of the matrix metalloproteinase MMP-2 and the adhesion molecule VCAM-1. Moreover, we found both immune cell types to affect trophoblast proliferation and viability and DC to reduce trophoblast invasion. These data suggest that Treg and DC participate in adequate placenta formation by regulating trophoblast functionality. In a second experimental setting using a more physiological ex vivo mouse autologous implantation model, we confirmed Treg and DC as critical players during embryo implantation. Depletion of both immune cell types before implantation using transgenic mouse strains resulted in blastocysts with delayed development and an impaired capability to attach to autologous endometrial epithelial cells. In agreement with our human data, DC seem to reduce trophoblast outgrowth, whereas Treg rather contribute to trophoblast expansion. The latter finding might be supported by hCG. In summary, our research study provided novel insights into immune-regulated mechanisms during embryo implantation.

Publications

• Human Chorionic Gonadotropin-Mediated Immune Responses That Facilitate Embryo Implantation and Placentation. Frontiers in Immunology, 10.
  Schumacher, Anne & Zenclussen, Ana C.
  
• Human Miscarriage Is Associated With Dysregulations in Peripheral Blood-Derived Myeloid Dendritic Cell Subsets. Frontiers in Immunology, 10.
  Ehrentraut, Stefanie; Sauss, Karoline; Neumeister, Romy; Luley, Lydia; Oettel, Anika; Fettke, Franziska; Costa, Serban-Dan; Langwisch, Stefanie; Zenclussen, Ana Claudia & Schumacher, Anne
  
• Human chorionic gonadotropin promotes murine Treg cells and restricts pregnancy-harmful proinflammatory Th17 responses. Frontiers in Immunology, 13.
  Lentz, Lea S.; Stutz, Annika J.; Meyer, Nicole; Schubert, Kristin; Karkossa, Isabel; von Bergen, Martin; Zenclussen, Ana C. & Schumacher, Anne
  
• Insights into Early-Pregnancy Mechanisms: Mast Cells and Chymase CMA1 Shape the Phenotype and Modulate the Functionality of Human Trophoblast Cells, Vascular Smooth-Muscle Cells and Endothelial Cells. Cells, 11(7), 1158.
  Zhang, Ningjuan; Schumacher, Anne; Fink, Beate; Bauer, Mario; Zenclussen, Ana Claudia & Meyer, Nicole