Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells.

PROBLEM: Preeclampsia affects 3-17% of pregnancies worldwide and has serious consequences for both the mother and the fetus. As maternal-fetal immune tolerance is bidirectional, fetal immunopathology may play a significant role in the pathogenesis of pregnancy disorders. Nevertheless, the impact of preeclampsia on the fetal immune system is unclear. METHOD OF STUDY: In this case-control study, we examined the phenotype of innate and adaptive immune cells from the cord blood of 3rd trimester babies born to healthy mothers and compared them to cord blood from 3rd trimester babies born to mothers with symptomatic preeclampsia. RESULTS: The ratio of CD56hi CD16- non-activated/regulatory NK cells to CD56lo CD16+ activated/effector NK cells as well as the proportion of CD4+ T cells was significantly decreased in the cord blood of babies born to preeclamptic mothers. The percentage of FoxP3+ Treg, especially the FoxP3lo populations (resting Treg and cytokine Treg), were significantly reduced. Importantly, this reduction in FoxP3+ Treg affected the ratio of CD8+ effector T cells per FoxP3+ Treg in the cord blood of babies born to preeclamptic mothers. CONCLUSION: These observations indicate that there are significant fetal immune system derangements during preeclampsia.

Normal human pregnancy results in maternal immune activation in the periphery and at the uteroplacental interface.

Pregnancy poses a unique challenge to the human immune system: the semi-allogeneic fetus must be protected from maternal immune attack while immunity towards pathogens is maintained. Breakdown in maternal-fetal tolerance can lead to pregnancy-specific diseases with potentially high degrees of morbidity and mortality for both the mother and her fetus. Various immune cell-types could mediate these functions, but a comprehensive evaluation of the peripheral and local maternal T cell and regulatory T cell compartments in normal human pregnancy is lacking. In this case-control study, we apply the Human Immunology Project Consortium proposed gating strategies to samples from healthy 3rd trimester human subjects compared with healthy non-pregnant controls. The proportions of HLA-DR+ and CD38+ effector- and effector memory CD8 T cells are significantly increased in the peripheral blood of pregnant women. Utilizing a novel technique that takes advantage of the standard protocol for intrauterine cleanup after cesarean section, we isolate lymphocytes resident at the uteroplacental interface (UPI). At the UPI, the CD4 and CD8 T cell compartments largely mirror the peripheral blood, except that the proportion of HLA-DR+ activated T regulatory cells is significantly increased in direct proportion to an observed increase in the number of activated CD8 T cells. We find that cryopreservation and delayed sample processing (>12 hours) decreases our ability to identify regulatory T cell subsets. Further, the Consortium proposed method for Treg identification underrepresents Resting and Cytokine Tregs compared with Activated Tregs, thus skewing the entire population. Better understanding of the changes in the immune system during pregnancy in the peripheral blood and at the uteroplacental interface are essential for progress in treatment of pregnancy diseases such as pre-eclampsia and recurrent miscarriage.