The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

First trimester trophoblast cells induce regulatory properties in B cells (#379)

Ruth Marian Guzman-Genuino 1 2 3 , Tanya Dimova 3 , Yuan You 3 , Gil Mor 3 , John D Hayball 1 , Kerrilyn R Diener 1 2
  1. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
  2. Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
  3. Yale School of Medicine , Yale University, New Haven, Connecticut, United States of America

A successful outcome to pregnancy is critically dependent upon the initiation of maternal immune tolerance upon contact with foreign paternal antigens at insemination and during implantation, a process that requires optimal expansion of regulatory T cells and tolerogenic dendritic cells. Recently IL-10-producing regulatory B cells (Bregs) have also been implicated as players in maternal tolerance. Clinically, significantly higher numbers of circulating Bregs are found in women who experienced normal pregnancies compared to those who had suffered spontaneous abortions. In abortion-prone mouse models, pregnancy can be rescued with early administration of Bregs. Furthermore, our mouse studies have shown a significant increase in uterine Breg frequency during early implantation. Therefore we hypothesized that during implantation, the conceptus influences the maternal B cell profile to acquire regulatory properties. To test this, the human trophoblast cell line SWAN-71 was co-cultured with human peripheral blood B cells. Results show that trophoblast cells enriched memory and plasmablast-like B cells, and increased the frequency of IL-10-producing cells within the transitional B cell subpopulation. These ‘educated’ B cells also upregulated IL-10 and TGFβ mRNA expression, all hallmarks of regulatory B cells. To confirm a regulatory function, we show that these B cells modulate the capacity of stromal cells to recruit CD8+ T cells under inflammatory conditions by inhibiting IP-10 production and inducing TGFβ release. Soluble factors from educated B cells also altered the CD4+/CD8+ T-cell ratio as well as the corresponding cytokine profile. Lastly, using trophoblast spheroids as an in vitro implantation model, we demonstrate that the addition of conditioned media from educated B cells protect the spheroid from damage and facilitate migration and invasion, despite the presence of deleterious T-cell cytokines. Thus, we posit that first trimester trophoblast cells can educate B cells to acquire regulatory properties which contribute in securing successful implantation during pregnancy.