Mechanisms promoting pregnancy success: Dendritic cells as intermediators between Human Chorionic Gonadotropin and Regulatory T cells

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Infertility or miscarriage can no longer be considered a personal problem but rather a public health problem. The inability to conceive a child not only results in personal conflicts but has also been associated with psychiatric disorders. Beside intensive costs for infertility treatments there are further costs involved managing mental health complications. For this reason a detailed understanding of mechanisms resulting in successful pregnancies is essential. Ultimately this will advance therapeutic interventions for patients suffering infertility or miscarriages and reduce the number of women developing mental disorders due to reproductive failure. During pregnancy the maternal immune system is challenged by the presence of foreign paternal antigens expressed by the semi-allogeneic fetus. Fetal survival within the hostile maternal uterus can only be achieved by a fine regulation of maternal immune responses towards fetal alloantigens. Here, pregnancy hormones like the human Chorionic Gonadotropin (hCG) are proposed to be important immune modulators. In previous studies we showed that hCG supports fetal tolerance by enhancing the number and activity of regulatory T cells (Treg). However, it has not been clarified whether hCG influences Treg directly or via indirect pathways. Tolerogenic dendritic cells (DCs) were described as potent inducers of Treg and there is evidence that hCG may retain a tolerogenic profile of DCs. However, in vitro data describing an influence of hCG on DCs is inconsistent and in vivo data is limited. Moreover, to the best of our knowledge there are no available studies employing human samples in the literature that confirm DCs as direct intermediators between hCG and Treg during pregnancy. Thus, the overall aim of our planned research is to test the hypothesis that hCG indirectly influences Treg via regulation of DCs during human pregnancy. To achieve this we will (1) test the influence of hCG on the phenotype and functionality of human peripheral DCs, (2) evaluate the effect of different hCG isoforms on the phenotype and functionality of human peripheral DCs (3) test whether trophoblasts from patients having spontaneous abortions or normal pregnant women will differently influence human peripheral DC behavior and (4) determine whether DC modulation by trophoblasts from different pregnancy outcomes will influence Treg induction. Thereby, our proposed research will advance the state-of-the-art in the reproductive immunology field by gaining more knowledge about the basic mechanisms supporting fetal tolerance. Moreover, we strongly believe our research to have wider implications in other immune-related fields such as organ transplantation, autoimmunity and cancer. Finally, we hope that our research will build bridges between basic research and clinical application resulting in advanced therapeutic interventions for patients suffering infertility and miscarriages.