Dynamic changes in immune populations at the fetomaternal interface during term and preterm birth

Abstract

Abstract The biologic mechanisms by which birth is initiated are unknown. Recent evidence suggests that the immune system may modulate gestational length. We previously established that maternal immune cells enter the placenta by mid gestation and change in composition near term. We hypothesize that preterm birth also involves immunologic alterations at the fetomaternal interface. To test this hypothesis, we used an established model of inflammation-induced preterm birth. Pregnant mice received intrauterine injections (IUI) of lipopolysaccharide (LPS) (250μg/100μl) (N=8) or saline (100μl) (N=7) on embryonic day 15 (E15). Control mice, without IUI, were sacrificed on E15 (N=7) and E19 (N=7). (Term gestation is E19.5.) Maternal blood, spleen, uterine implantation sites, and placentae were collected, processed, and analyzed for immune cells by flow cytometry (CD45, Ly6G, CD11c, CD11b, CD103, F4/80, IA/IE, CD3, CD4, CD8, CD19, CD49b, TCR γ/δ, FoxP3, IL-17). At E19, term gestation, the frequencies of multiple immune cell types decrease in the placenta: regulatory T cells (1.6 to 0.8%; p=0.0004), NK cells (2.6 to 1.5%; p=0.009), CD11c+ myeloid cells (8.6 to 5.5%; p=0.013), and CD103+ dendritic cells (0.43 to 0.25%; p=0.013). Only NK cells decrease near term in the uterus (9.5 to 1.6%; p=0.011). In contrast, during inflammation-induced preterm birth, macrophages decrease in the placenta (4.4 to 2.5%; p=0.042) and neutrophils increase in the uterus (26 to 52%; p=0.0006). These findings demonstrate that the immune composition of the fetomaternal interface shifts prior to birth. However, both the cell types and location of this shift differ between term and preterm birth, suggesting distinct immunologic mechanisms contribute to these processes.