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

不孕不育或流产不再被视为个人问题，而是一个公共卫生问题。不能怀上孩子不仅会导致个人冲突，还会导致精神障碍。除了不孕不育治疗的高成本外，还有更多的成本涉及管理心理健康并发症。因此，对导致成功怀孕的机制有详细的了解是至关重要的。最终，这将促进对不孕不育或流产患者的治疗干预，并减少因生殖失败而患上精神障碍的妇女人数。在怀孕期间，母体免疫系统受到半异基因胎儿表达的外源父源抗原的挑战。在敌意的母体子宫内的胎儿存活只能通过对母体对胎儿同种异体抗原的免疫反应的精细调节来实现。在这里，妊娠激素，如人绒毛膜促性腺激素(HCG)被认为是重要的免疫调节剂。在以前的研究中，我们发现hCG通过增加调节性T细胞(Treg)的数量和活性来支持胎儿耐受。然而，目前还不清楚hCG是直接影响Treg还是通过间接途径影响Treg。耐受性树突状细胞(DC)被描述为Treg的有效诱导者，有证据表明hCG可能保留DC的耐受性特征。然而，描述hCG对DC影响的体外数据是不一致的，体内数据也是有限的。此外，据我们所知，在文献中没有使用人类样本的现有研究证实DC是怀孕期间hCG和Treg之间的直接中介。因此，我们计划的研究的总体目标是检验hCG通过调节人类怀孕期间的DC间接影响Treg的假设。为了实现这一目标，我们将(1)检测hCG对人外周血树突状细胞表型和功能的影响，(2)评估不同hCG亚型对人外周血树突状细胞表型和功能的影响，(3)检测自然流产患者和正常孕妇的滋养层细胞是否会对人外周血树突状细胞的行为产生不同的影响，以及(4)确定不同妊娠结局的滋养层细胞对DC的调节是否会影响Treg诱导。因此，我们提出的研究将通过获得更多关于支持胎儿耐受的基本机制的知识，推动生殖免疫学领域的最新进展。此外，我们坚信，我们的研究将在器官移植、自身免疫和癌症等其他免疫相关领域产生更广泛的影响。最后，我们希望我们的研究将在基础研究和临床应用之间架起桥梁，从而为遭受不孕和流产的患者提供先进的治疗干预措施。

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.