IFPA Senior Award Lecture: Reproductive immunology in perspective--reprogramming at the maternal-fetal interface

Abstract

Involvement of the maternal and fetal immune systems in the events of pregnancy was generally overlooked by reproductive biologists until the mid-twentieth century when many landmark explorations were reported. Now, more than half a century later, it is well understood that with the initiation of pregnancy, immune cells in mammalian uteri are reprogrammed, losing their cytotoxic potential and providing an immunosuppressive environment suitable for harboring the genetically different fetus. We propose that it is the placenta that is mainly responsible for this conversion and maintenance throughout pregnancy. Studies in our laboratory indicate that trophoblast-derived soluble HLA-G has a subtle but well defined role in programming uterine placental macrophages, a potentially destructive immune cell population. Thus, placental HLA-G plays a critical role in assuring that the developing fetus emerges unscathed at parturition.

Fig. 1. Infiltrating cytotrophoblast cells and maternal uterine macrophages reside side by side in early (8 week) human decidua

Macrophages were stained with anti-CD14 (green, arrows) and cytotrophoblasts (red, arrowheads) were stained with anti-cytokeratin-8. The figure also reveals that glandular epithelial cells stain orange in this double stain. Confocal microscopy; original magnifications (A) x200 (bar, 50 μm) and (B) x400 (bar, 20μm).

Fig. 2. HLA-G5 in pregnancy sera

Throughout the three trimesters of pregnancy, maternal blood contains HLA-G5 but little HLA-G6. Values were obtained in capture ELISA assays against monoclonal antibody 1-2C3 (IgG1, anti-HLA-G5) and monoclonal antibody 26-2H11 (IgG1, anti-HLA-G6) [15]. Levels of HLA-G5 increased through pregnancy. * = P<0.05 when levels in pregnancy sera were compared with levels in nonpregnant female sera.