Immune Modulatory Effects of Human Chorionic Gonadotropin on Dendritic Cells Supporting Fetal Survival in Murine Pregnancy.

Dominique Dauven,Stefanie Langwisch,Stefanie Ehrentraut,Ana Claudia Zenclussen,Anne Schumacher

doi:10.3389/fendo.2016.00146

Dominique Dauven, Stefanie Langwisch + Show 3 more

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https://doi.org/10.3389/fendo.2016.00146

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Abstract

Dendritic cells (DCs) are critically involved in the determination of immunity vs. tolerance. Hence, DCs are key regulators of immune responses either favoring or disfavoring fetal survival. Several factors were proposed to modulate DC phenotype and function during pregnancy. Here, we studied whether the pregnancy hormone human chorionic gonadotropin (hCG) is involved in DC regulation. In vitro, bone marrow-derived DCs (BMDCs) were stimulated in the presence or absence of urine-purified or recombinant hCG (rhCG) preparations. Subsequently, BMDC maturation was assessed. Cytokine secretion of activated BMDCs and their capability to enforce TH1, TH2, TH17, or Treg cell differentiation was determined after rhCG treatment. Moreover, the in vivo potential of hCG-modulated BMDCs to influence pregnancy outcome, Treg cell number, and local cytokine expression was evaluated after adoptive transfer in a murine abortion-prone model before and after conception. Both hCG preparations impaired the maturation process of BMDCs. rhCG treatment did neither alter cytokine secretion by BMDCs nor their ability to drive TH1, TH2, or TH17 differentiation. rhCG-treated BMDCs augmented the number of Treg cells within the T cell population. Adoptive transfer of rhCG-treated BMDCs after conception did not influence pregnancy outcome. However, transfer of hCG-treated BMDCs prior to mating had a protective effect on pregnancy. This positive effect was accompanied by increased Treg cell numbers and decidual IL-10 and TGF-β expression. Our results unveil the importance of hCG in retaining DCs in a tolerogenic state, thereby promoting Treg cell increment and supporting fetal survival.

Highlights

Dendritic cells (DCs) are situated at the interface between the innate and the adaptive immune system and are, critically involved in the initiation or suppression of adaptive immune responses
In addition to urine-purified hCG (uhCG), we tested the effects of recombinant hCG (rhCG) on bone marrow-derived DCs (BMDCs) stimulated with LPS and IFN-γ for 24 h
After 24 h of culture, we observed a significant increase in the number of mature CD80+MHCII+ BMDCs after LPS and IFN-γ stimulation (Figures 1A,B)

Summary

Introduction

Dendritic cells (DCs) are situated at the interface between the innate and the adaptive immune system and are, critically involved in the initiation or suppression of adaptive immune responses. Human DCs represent approximately 1.7% of all CD45+ cells in the decidua and the vast majority displays a myeloid phenotype [1]. Kämmerer and colleagues described a unique DC population in the human decidua displaying an immature phenotype with a high proliferative potential and low T cell stimulatory capacity [2]. The highest number of total DCs could be detected at early pregnancy stages where the average density of CD11c+ cells was 1.3% of all nucleated cells in the decidua. One study by Plaks and colleagues confirmed the indispensable role of murine uterine DCs for the implantation process [6], while two other human studies proposed an association between an elevated number of mature DCs and recurrent spontaneous abortions [7, 8]. The factors and underlying mechanisms affecting the phenotype and function of DCs during pregnancy are still not completely understood

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