Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. There are unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall. Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. It is increasingly evident that the gestational uterine microenvironment is characterized, at least in part, by the differential expression and secretion of chemokines that induce selective trafficking of leukocyte subsets to the maternal-fetal interface and regulate multiple events that are closely associated with normal pregnancy. Here, we review the expression and function of chemokines and their receptors at the maternal-fetal interface, with a special focus on chemokine as a key component in trophoblast invasiveness and placental angiogenesis, recruitment and instruction of immune cells so as to form a fetus-supporting milieu during pregnancy. The chemokine network is also involved in pregnancy complications.

Decidual natural killer (dNK) cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) are expressed on over 60% of dNK cells. Tim-3 1 dNK cells display higher interleukin (IL)-4 and lower tumor necrosis factor (TNF)-a and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 (Gal-9) and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper (Th)2-type cytokines were decreased and Th1-type cytokines were increased in Tim-3 1 but not Tim-3 2 dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.

Mesenchymal stem cells (MSCs), which are pluripotent cells with immunomodulatory properties, have been considered good candidates for the therapy of several immune disorders, such as inflammatory bowel diseases, concanavalin A-induced liver injury, and graft-versus-host disease. The embryo is a natural allograft to the maternal immune system. A successful pregnancy depends on the timely extinction of the inflammatory response induced by embryo implantation, followed by the switch to a tolerant immune microenvironment in both the uterus and the system. Excessive infiltration of immune cells and serious inflammatory responses are triggers for embryo rejection, which results in miscarriage. Here, we demonstrated that adoptive transfer of MSCs could prevent fetal loss in a lipopolysaccharide (LPS)-induced abortion model and immune response-mediated spontaneous abortion model. The immunosuppressive MSCs alleviated excessive inflammation by inhibiting CD4 + T cell proliferation and promoting the decidual macrophage switch to M2 in a tumor necrosis factor-stimulated gene-6 (TSG-6)-dependent manner. Cell-tocell contact with proinflammatory macrophages increased the TSG-6 production by the MSCs, thereby enhancing the suppressive regulation of T cells and macrophages. Moreover, proinflammatory macrophages in contact with the MSCs upregulated the expression of CD200 on the stem cells and facilitated the reprogramming of macrophages towards an anti-inflammatory skew through the interaction of CD200 with CD200R on proinflammatory macrophages. Therefore, the results demonstrate that a TSG-6mediated paracrine effect, reinforced by cell-to-cell contact between MSCs and proinflammatory macrophages, is involved in the mechanism of MSC-mediated abortion relief through the induction of immune tolerance. Our study also indicates the potential application of MSCs in clinical recurrent miscarriages.

Pregnancy loss occurs in about 15% of clinically recognized pregnancies, and defective maternal-fetal immune tolerance contributes to more than 50% of these events. We found that signaling by the type I membrane protein T cell immunoglobulin and mucin-containing protein 3 (Tim-3) in natural killer (NK) cells had an essential protective role during early pregnancy. Tim-3 on peripheral NK (pNK) cells was transiently increased in abundance during the first trimester of pregnancy, which depended on interleukin-4 (IL-4)-signal transducer and activator of transcription 6 (STAT6) and progesterone signaling. Tim-3 pNK cells displayed immunosuppressive activities, including the production of anti-inflammatory cytokines and the induction of regulatory T cells (T) in a transforming growth factor-β1 (TGF-β1)-dependent manner. Tim-3 on pNK cells was stimulated by its ligand galectin-9 (Gal-9), leading to signaling by the kinases c-Jun N-terminal kinase (JNK) and AKT. In recurrent miscarriage (RM) patients, Tim-3 abundance on pNK cells was reduced and the immunosuppressive activity of Tim-3 pNK cells was impaired. Compared to Tim-3 pNK cells from donors with normal pregnancies, RM patient Tim-3 pNK cells exhibited changes in DNA accessibility in certain genetic loci, which were reversed by inhibiting accessible chromatin reader proteins. Furthermore, Tim-3 pNK cells, but not Tim-3 pNK cells, reduced fetal loss in abortion-prone and NK cell-deficient mice. Together, our findings reveal a critical role for Tim-3-Gal-9 signaling-mediated immunoregulation by pNK cells in maternal-fetal immune tolerance and suggest that Tim-3 abundance on pNK cells is a potential biomarker for RM diagnosis.