| Successful human pregnancy requires close association between fetal and maternal cells, presenting an immunological paradox; maternal immune cells are exposed to fetal (and therefore paternal) antigens, establishing the potential for rejection of the fetus. The goal of this work is to understand the mechanisms of immunologic privilege of the fetus and its associated tissues. One factor proposed to play a role in establishing this immunologic privilege is human leukocyte antigen (HLA)-G, an immune-suppressive class Ib molecule expressed by fetal trophoblasts. Potential cellular targets of HLA-G have been identified based on expression of its receptors, leukocyte immunoglobulin-like receptor (LILR)B1 and LILRB2. Immune-suppressive effects of HLA-G on the functions of natural killer cells, cytotoxic, and helper T cells continue to be well-studied. The work presented here is the only study of HLA-G modulation of monocytes/macrophages, powerful leukocytes residing at the maternal-fetal interface throughout pregnancy.; We first characterized the phenotype of term decidual macrophages and found they are IFN-gamma-activated but produce anti-inflammatory cytokines, IL-10 and TGF-beta1. To determine which factors are responsible for programming these cells, we compared the phenotype of blood monocytes that had undergone in vitro activation and differentiation and found that some, but not all, of the characteristics of decidual macrophages could be induced in vitro, supporting the idea that tissue-specific factors are important in shaping the phenotype of decidual macrophages. We next tested whether HLA-G is responsible for decidual macrophage programming, and we found that treatment of the U937-myelomonocytic cell line with eukaryotic-recombinant HLA-G induced TGF-beta1 production. Finally, to establish spatial and temporal relationships between HLA-G-producing trophoblasts and maternal cells, we studied the localization of the HLA-G receptors, LILRB1 and LILRB2, in tissues from first, second, and third trimester pregnancies. We found that both receptors were present in stromal cells, which include many leukocyte subpopulations. However, we also found LILRB2 in vascular cells of the decidua, placenta, and umbilical cord, suggesting potentially new functions for HLA-G. Overall, these studies add to the understanding of HLA-G as an immuno-modulator at the maternal-fetal interface, and establish a new direction for research involving vascular biology. |
