The maternal-fetal interface is replete with immune cells which cross-talk with hormonal, endocrine, and angiogenic regulators to program a normal pregnancy outcome. Among immune cell types, regulatory T cells (Tregs), a specialized CD4 T cell subset phenotyped as CD4+
, play an important role in protecting the fetus by dampening harmful inflammatory immune responses at the maternal-fetal interface. It has been shown in humans [17
] that Treg numbers increase very early in pregnancy, peak during the early second trimester and then begin to decline until they reach pre-pregnancy levels. Tregs have also been shown to be crucial in immune tolerance of the fetus in the mouse pregnancy model [18
] and also follow a gestational age-dependent presence in the uterus. Animal studies further indicate that tolerance to paternal antigens may be initiated during mating when seminal fluid and components of semen have been shown to trigger expansion of the Treg cell population [19
]. Further, it has been shown that Tregs migrate toward areas of hCG production [20
], indicating that in normal pregnancy, these cells may be attracted to hCG produced by trophoblasts at the maternal-fetal interface ensuring immune tolerance of the fetus. However, if hCG undergoes dysregulation during pregnancy, its control over immune tolerance pathways may be impaired.
Interleukin-10 (IL-10) and the tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) are two important immune regulators. Levels of IL-10, a key immunosuppressant, increase in early pregnancy and remain elevated until the onset of labor [21
], possibly regulating maternal immunity and allowing acceptance of the fetal allograft. As shown by our studies, IL-10 can regulate uNK cell maintenance and control their cytotoxic functions in response to pro-inflammatory challenges during pregnancy [22
]. Further, decidual Tregs can inhibit immune stimulation of T cells through IL-10 production [24
]. The temporal expression of IDO regulates the Tregs and prevents them from being converted to pro-inflammatory Th17 (T helper 17) cells [25
]. hCG is able to stimulate IL-10 production in bone marrow derived dendritic cells (BMDC) from mice [26
]. This same study found that treatment of BMDC with hCG and interferon gamma (IFN-γ) increased IDO mRNA production and enzyme activity, raising the question of whether hCG can stimulate IL-10 production and IDO activity in trophoblasts as well. Our unpublished results suggest that hCG can rescue pregnancy in IL-10−/−
mice by subverting production of anti-angiogenic factors and by replenishing uterine immune cells.
It is noteworthy that hCG is now considered as an angiogenic factor [27
] and thus may regulate an endovascular cross-talk between trophoblasts, endothelial cells, and immune cells represented by uNK cells. These specialized cells have been shown to play an important role in spiral artery remodeling and trophoblast invasion at least in animal studies [29
]. We have recently demonstrated that vascular endothelial growth factor C (VEGF C) production by uNK cells is responsible for their non-cytotoxic activity, and that VEGF C producing uNK cells support endovascular processes in vitro
]. It is possible that the tolerogenic phenotype of uterine NK cells during early decidualization is be influenced by hCG through stimulation of the quiescent angiogenic machinery. Recent studies indicate that the uNK cells are indeed influenced by hCG. Kane et al
showed that hCG induces proliferation of human uNK cells, by interacting through the mannose receptor rather than the LH/hCG receptor [32
]. Importantly, deglycosylated hCG was not able to bind to mannose receptors on uNK cells, again emphasizing the importance of carbohydrate patterns in the function of hCG.