Human Chorionic Gonadotropin acts as a central regulator of adaptive immune responses during early pregnancy safeguarding fetal survival

Abstract

Abstract A perfect interplay between the endocrine system and the maternal immune system is pivotal for early fetal tolerance induction. Particularly, the placenta-derived hormone human chorionic gonadotropin (hCG) that is secreted during early pregnancy stages and is suggested to regulate pro- and anti-inflammatory maternal immune responses. However, the precise mechanisms underlying hCG-driven immunoregulation are far from being understood. Thus, we performed several studies to illuminate the participation of hCG in immunomodulation with a specific focus on T and B cell responses. We included human and mouse material in our studies to analyze the influence of hCG on the generation, plasticity and functionality of regulatory T (Treg) cells, Th17 cells and B cells using different in vitro assays. In vivo, we applied hCG during the peri-implantation period into abortion-prone mice and analyzed Treg proportions and activity. Our in vitro results revealed that hCG attracts human Treg, promotes formation of human and mouse Treg and increases T cell suppressive activity in both species. Moreover, hCG inhibits mouse Th17 differentiation and induces Th17 cells with anti-inflammatory phenotypes in the mouse system. Human B cells adopt a regulatory phenotype and start to secrete fetal-protective asymmetric antibodies upon hCG stimulation in vitro. In vivo, hCG application into abortion-prone mice restored Treg levels, augmented Treg suppressive activity and rescued fetuses from rejection. In summary, our findings suggest that hCG contributes to early fetal tolerance induction by shifting maternal adaptive immune responses towards an anti-inflammatory profile.