Immune Privilege of the Mammalian Fetus
In eutherian mammals (mammals with placentae), the fetus expresses paternally inherited genes that are foreign to the mother, but fetuses are not normally rejected by the mother. In essence, the fetus is a naturally occurring allograft, but one that is protected from graft rejection. It is clear that the mother is exposed to fetal antigens during pregnancy because maternal antibodies against paternal major histocompatibility complex (MHC) molecules are easily detectable. Obviously, there has been very strong selective pressure that has led to the evolution of mechanisms that protect the fetus from the maternal immune system, so called fetal tolerance, yet these mechanisms remain poorly understood. Many different special molecular and barrier features of the placenta and local immunosuppression may contribute.
The anatomic location of the fetus is a critical factor in the absence of rejection. For example, pregnant animals are able to recognize and reject allografts syngeneic to the fetus placed at extrauterine sites without compromising fetal survival. Wholly allogeneic fetal blastocysts that lack maternal genes can success fully develop in a pregnant or pseudopregnant mother. Thus, neither specific maternal nor paternal genes are necessary for survival of the fetus. Hyperimmunization of the mother with cells bearing paternal antigens does not compromise placental and fetal growth.
The failure to reject the fetus has focused attention on the region of physical contact between the mother and fetus. The fetal tissues of the placenta that most intimately contact the mother are composed of vascular trophoblasts, which are exposed to maternal blood for the purposes of mediating gas exchange and nutrient supply, or implantation site trophoblasts, which diffusely infiltrate the uterine lining (decidua) for purposes of anchoring the placenta to the mother.
One simple explanation for fetal survival is that trophoblast cells fail to express paternal MHC molecules. MHC class II molecules have not been detected on trophoblast cells. In mice, cells of implantation trophoblast, but not of vascular trophoblast, do express paternal MHC class I molecules. In humans, the situation may be more complex in that trophoblast cells express mainly a nonpolymorphic class I molecule called HLA-G. This molecule may be involved in protecting trophoblast cells from maternal NK cell–mediated lysis. A specialized subset of NK cells called uterine NK cells are the major type of lymphocyte present at implantation sites, and interferon-γ (IFN-γ) production by these cells is essential for decidual development. The way in which uterine NK cells are stimulated and their role in maternal responses to fetal alloantigens are not known. Even if trophoblast cells do express classical MHC molecules, they may lack costimulator molecules and fail to act as antigen-presenting cells.
The uterine decidua may be a site where immune responses are functionally inhibited. In support of this idea is the observation that mouse decidua is highly susceptible to infection by Listeria monocytogenes and cannot support a delayed-type hypersensitivity response. The basis of immunologic privilege is clearly not a simple anatomic barrier because maternal blood is in extensive contact with trophoblast cells. Rather, the immune barrier is likely to be created by functional inhibition, attributable to multiple mechanisms.
Maternal tolerance of the fetus may be mediated by Tregs. Experimental evidence suggests that Treg cells prevent immune reactions against paternally derived antigens that are not expressed in the mother. Fetal antigens induce long-lived FOXP3+ Tregs in mice, and depletion of these cells results in fetal loss. During pregnancy, systemic and decidual Tregs increase in mothers and abundant Tregs are found in the fetus. Indeed, eutherian mammals have evolved a transposon-mediated change in a regulatory sequence of the Foxp3 gene that allows these species to generate stable peripheral Tregs. This regulatory region of Foxp3 is not found in earlier vertebrates or even in metatherian mammals such as kangaroos and wallabies that carry their young. The contribution of Tregs in human pregnancy is under active investigation, as is the possibility of Treg defects as the basis for recurrent spontaneous abortions.
Immune responses to the fetus may be regulated by local concentrations of tryptophan and its metabolites in the decidua, which inhibit T-cell responses. The enzyme IDO is made in the placenta and catabolizes tryptophan, generating a by-product, kynurenine. Tryptophan is required for proliferating cells, including lymphocytes, and kynurenine is toxic to these cells. These observations led to the hypothesis that T-cell responses to the fetus are normally blocked because decidual tryptophan levels are kept low or the levels of toxic metabolites produced by IDO are high.
Several other mechanisms may also dampen the maternal immune response to the fetus, including FAS-L expression by fetal trophoblast cells that promote apoptosis of activated FAS expressing maternal lymphocytes, and the induction by galectin-1 in the decidua of tolerogenic DCs that facilitate Treg generation.
Passive Immunity in the Fetus and Newborn
Fetal and neonatal mammals cannot make their own IgG antibodies, but they defend against infection by maternal IgG transported across the placenta into the fetal circulation and by IgA in breast milk ingested by the nursing infant. Transport of maternal IgG across the placenta is mediated by the IgG-specific neonatal Fc receptor (FcRn). This receptor is expressed on syncytiotrophoblast cells of the placental villi, which form a barrier between the maternal and fetal tissues. FcRn binds IgG from the maternal blood present in the intervillous spaces, and the receptor mediates transcytosis of the IgG to the fetal side of the syncytiotrophoblast, where it is released into the villous stroma. The IgG is then transported across fetal capillary endothelium into the fetal circulation (Fig. 1A). Thus, a newborn contains essentially the same IgG antibodies as the mother. Protective levels of maternal IgG are maintained for about 6 months, after which time the majority of circulating IgG is made by the baby (see Fig. 1B). This transition period is a time of enhanced susceptibility of babies to infections because they will not have accumulated memory B cells and long-lived plasma cells from prior infections. The transepithelial transport of maternal IgA into breast milk depends on the poly-Ig receptor described earlier this chapter, and the ingested IgA can neutralize pathogenic organisms that attempt to colonize the infant’s gut.
Fig1. Fetal and neonatal immunity mediated by passive transfer of maternal immunoglobulin G (IgG). (A) IgG is transported from maternal blood in the intervillous spaces of the placenta across the placental syncytial trophoblast cells by the neonatal Fc receptor (FcRn), and then transported across fetal vessel endothelial cells into the fetal circulation. (B) Serum Ig levels in the fetus and neonate. Maternally derived IgG is shown by the dashed brown line, neonate derived IgG by the solid green line, and the neonate plus maternally derived total IgG by the solid red line. The neonate starts making IgG soon after birth, but the loss of maternal IgG and the slow increase in neonatally derived IgG results in a nadir of blood IgG concentration at about 6 months of age. The fetus starts making IgM late in pregnancy, and the IgM concentrations approach adult levels more quickly in the baby than IgG. Nonetheless, these IgMs will not be specific for the wide range of microbes that the maternal IgGs will recognize, and the baby has a heightened risk for infection at the time of the IgG nadir. IgA levels in the baby take longer to reach adult levels than either IgM or IgG, but maternal IgA in breast milk can provide passive intestinal immunity in nursing babies.
