Mechanisms promoting pregnancy success: Dendritic cells as intermediators between Human Chorionic Gonadotropin and Regulatory T cells
Final Report Abstract
Pregnancy is characterized by finely regulated immunological adaptions that allow the persistence of the foreign fetal antigens in the maternal womb. Hereby, not only local immune cell populations residing directly at the fetal-maternal interface but also immune cell types circulating in the periphery get in direct contact to fetal structures and are able to react towards them. Thus, pregnancy-driven immunological adjustments take place locally and peripherally and dysregulations in uterine as well as circulating immune responses may interfere with normal pregnancy progression. As one of the first immune cell types encountering fetal antigens, dendritic cells (DCs) possess the capacity to induce either immunity or tolerance towards the fetus. Their behavior highly depends on the maturation state and cytokine secretion pattern. Notably, data referring to the distribution and the phenotype of peripheral blood DC (PBDC) subsets during normal and pathologic pregnancies are rather inconsistent which might be due to the different DC characterization strategies applied in the past. Moreover, the factors regulating the distinct PBDC subsets are still ill defined. In previous murine studies, we suggested the placenta-derived hormone human Chorionic Gonadotropin (hCG) to retain DCs in a tolerogenic state, thereby inducing pregnancy-protective regulatory T cells (Treg) and maintain fetal tolerance. In our current research project, we aimed to test the hypothesis that hCG modulates human PBDC subsets in such a way that these cells contribute to Treg induction during normal pregnancy. We addressed the following scientific questions: (1) does hCG influence the phenotype and functionality of human PBDCs (2) are PBDCs differentially regulated by various hCG isoforms (3) does the phenotype and the function of PBDCs change during normal pregnancy progression and in pathologic pregnancies and is this related to hCG and (4) does hCG-mediated PBDC modulation provoke Treg induction. Our findings suggest that during normal pregnancy progression PBDC subsets are differentially regulated depending on gestational age. Miscarriage seems to be associated with dysregulations in the frequencies and functionality of the myeloid PBDC subsets as well as with disturbances in Treg frequencies. However, we could not identify hCG as one of the key regulators responsible for the observed PBDC alterations. In the light of our results, we propose that under inflammatory conditions, hCG may contribute to the maintenance of the delicate balance between myeloid and plasmacytoid PBDCs and support the myeloid PBDC subset MDC1 in retaining a more immature, tolerogenic profile. However, under steady-state conditions and in cases were maturation is already fully achieved hCG is not able to change the phenotype of PBDCs. Furthermore, we suggest the existence of an interdependency between MDC1 and Treg during early pregnancy. However, hCG seems not to promote MDC1-driven Treg induction. Our findings advanced the state-of-the-art in the reproductive immunology field by gaining more knowledge about the regulation of PBDCs during pregnancy and about a potential participation of hCG in this regulation. Hereby, we hope that our data will in long-term contribute to improved therapeutic interventions for patients suffering from infertility and miscarriages. Moreover, we strongly believe that our results will have wider implications on basic research in other immune-related fields such as autoimmunity and cancer, where hCG has been proposed as an immune modulating target.
Publications
- Immune Modulatory Effects of Human Chorionic Gonadotropin on Dendritic Cells Supporting Fetal Survival in Murine Pregnancy. Front Endocrinol (Lausanne). 2016 Nov 15;7:146
Dauven D, Ehrentraut S, Langwisch S, Zenclussen AC, Schumacher A
(See online at https://doi.org/10.3389/fendo.2016.00146) - JEG-3 Trophoblast Cells Producing Human Chorionic Gonadotropin Promote Conversion of Human CD4+FOXP3- T Cells into CD4+FOXP3+ Regulatory T Cells and Foster T Cell Suppressive Activity. Biol Reprod. 2016 Mar 1;94(5):106
Poloski E, Oettel A, Ehrentraut S, Luley L, Costa SD, Zenclussen AC, Schumacher A
(See online at https://doi.org/10.1095/biolreprod.115.135541) - Maternal and fetal mechanisms of B cell regulation during pregnancy: human Chorionic Gonadotropin stimulates B cells to produce IL-10 while alpha-fetoprotein drives them into apoptosis. Front Immunol. 2016 Dec 8;7:495
Fettke F, Schumacher A, Canellada A, Toledo N, Bekeredjian-Ding I, Bondt A, Wuhrer M, Costa S-D, Zenclussen AC
(See online at https://doi.org/10.3389/fimmu.2016.00495) - Human Chorionic Gonadotropin as a Pivotal Endocrine Immune Regulator Initiating and Preserving Fetal Tolerance. Int J Mol Sci. 2017 Oct 17;18(10)
Schumacher A
(See online at https://doi.org/10.3390/ijms18102166) - Immune Cells at the Fetomaternal Interface: How the Microenvironment Modulates Immune Cells To Foster Fetal Development. J Immunol. 2018 Jul 15;201(2):325-334
Schumacher A, Sharkey DJ, Robertson SA, Zenclussen AC
(See online at https://doi.org/10.4049/jimmunol.1800058) - The pregnancy hormone human chorionic gonadotropin differentially regulates plasmacytoid and myeloid blood dendritic cell subsets. Am J Reprod Immunol. 2018 Apr;79(4):e12837
Sauss K, Ehrentraut S, Zenclussen AC, Schumacher A
(See online at https://doi.org/10.1111/aji.12837)
