Specific innate immune cells uptake fetal antigen and display homeostatic phenotypes in the maternal circulation

Abstract

Pregnancy represents a period when the mother undergoes significant immunological changes to promote tolerance of the fetal semi‐allograft. Such tolerance results from the exposure of the maternal immune system to fetal antigens (Ags), a process that has been widely investigated at the maternal‐fetal interface and in the adjacent draining lymph nodes. However, the peripheral mechanisms of maternal‐fetal crosstalk are poorly understood. Herein, we hypothesized that specific innate immune cells interact with fetal Ags in the maternal circulation. To test this hypothesis, a mouse model was utilized in which transgenic male mice expressing the chicken ovalbumin (OVA) Ag under the beta‐actin promoter were allogeneically mated with wild‐type females to allow for tracking of the fetal Ag. Fetal Ag‐carrying Ly6G+ and F4/80+ cells were identified in the maternal circulation, where they were more abundant in the second half of pregnancy. Such innate immune cells displayed unique phenotypes: while Ly6G+ cells expressed high levels of MHC‐II and CD80 together with low levels of pro‐inflammatory cytokines, F4/80+ cells up‐regulated the expression of CD86 as well as the anti‐inflammatory cytokines IL‐10 and TGF‐β. In vitro studies using allogeneic GFP+ placental particles revealed that maternal peripheral Ly6G+ and F4/80+ cells phagocytose fetal Ags in mid and late murine pregnancy. Importantly, cytotrophoblast‐derived particles were also engulfed in vitro by CD15+ and CD14+ cells from women in the second and third trimester, providing translational evidence that this process also occurs in humans. Collectively, this study demonstrates novel interactions between specific maternal circulating innate immune cells and fetal Ags, thereby shedding light on the systemic mechanisms of maternal‐fetal crosstalk.

Pregnancy imparts distinct systemic adaptive immune function

“…[102][103][104][105] Indeed, prior studies in mice have demonstrated that innate immune cells in the periphery interact with fetal antigens throughout pregnancy, which was replicated in vitro by using human innate immune cells from the second and third trimesters. 103 Furthermore, cell-free fetal DNA (cffDNA) concentrations have been shown to increase in the maternal circulation in late gestation, which coincides with a pro-inflammatory shift in maternal immunity prior to parturition. [106][107][108][109] Specifically, cffDNA has been demonstrated to stimulate a monocyte response in the third trimester capable of activating bystander T cells.…”

“…86 Thus, the co-expression of CD69 and PD-1 likely indicates prolonged T-cell activation, as would be expected following chronic antigen exposure. Considering the presence of fetal antigens in the maternal circulation, 53,102,103 it is tempting to suggest that the increased proportion of CD4 + CD69 + PD-1 + T cells in pregnant women may reflect repeated exposure to such fetal antigens. [102][103][104][105] Indeed, prior studies in mice have demonstrated that innate immune cells in the periphery interact with fetal antigens throughout pregnancy, which was replicated in vitro by using human innate immune cells from the second and third trimesters.…”

“…Considering the presence of fetal antigens in the maternal circulation, 53,102,103 it is tempting to suggest that the increased proportion of CD4 + CD69 + PD‐1 + T cells in pregnant women may reflect repeated exposure to such fetal antigens 102–105 . Indeed, prior studies in mice have demonstrated that innate immune cells in the periphery interact with fetal antigens throughout pregnancy, which was replicated in vitro by using human innate immune cells from the second and third trimesters 103 . Furthermore, cell‐free fetal DNA (cffDNA) concentrations have been shown to increase in the maternal circulation in late gestation, which coincides with a pro‐inflammatory shift in maternal immunity prior to parturition 106–109 .…”

Deciphering maternal-fetal cross-talk in the human placenta during parturition using single-cell RNA sequencing

“…The maternal monocyte population detected in the placental tissues likely represents circulating cells present in the intervillous space ( 121 , 122 ). Previous reports have noted the enhanced activation of maternal circulating monocytes in the context of labor ( 93 , 123 , 124 ), likely driven by signals derived from the placental tissues ( 125 ), because such innate immune cells display up-regulated expression of activation markers and can phagocytose placenta-derived particles ( 126 ).…”

Pregnancy tailors endotoxin-induced monocyte and neutrophil responses in the maternal circulation

“…Pregnancy has been associated with increased expression of activation markers in peripheral innate immune cells [ 11 , 40 , 59 , 60 ], which is postulated to result from gestational factors such as the presence of placental microparticles and fetal cells in the maternal circulation [ 41 , 61 – 63 ]. Accordingly, a significant shift has been reported in the frequency of monocyte subsets from classical to intermediate, the latter displaying the surface signals of activation and differentiation in human pregnancy [ 64 ] and in an animal model [ 65 ].…”