Although many mechanisms are aimed at avoiding maternal immune recognition of the implanting fetus, research in both humans and animals indicates that immune responses to fetal antigens can be detected (216–218). Thus, the regulation of this response at the maternal–fetal interface may be critical. The concept that successful pregnancy requires some form of generalized suppression of maternal immune response is supported by reports that failure to downregulate maternal responses to recall antigens, such as tetanus toxoid and inﬂuenza, is associated with poor pregnancy outcome among recurrent pregnancy loss patients (219). Treg cells appear important in this respect (see above). So too do reproductive hormones. Reproductive hormones have dramatic effects on peripheral cell–mediated immunity, as demonstrated by well-documented and notable gender differences in immune responsiveness (220). The levels of these potentially immunosuppressive hormones are quite elevated in pregnant women. The fact that the levels of these hormones at the maternal–fetal interface may be far above those in the maternal circulation during pregnancy may explain an apparent inconsistency: overall immune responsiveness during pregnancy appears to change little, while local suppression at the maternal–fetal interface may be vital (221).
It has been suggested that the immunosuppressive effects of progesterone within the reproductive tract are at least partially responsible for the maintenance of the semiallogeneic implanting fetus (222). In vitro studies have shown that progesterone mediates its suppression of T-cell effector function by altering membrane-resident potassium channels and cell membrane depolarization. This action, in turn, affects intracellular calcium signaling cascades and gene expression and may be mediated by nonclassical steroid receptors or may not involve a receptor at all (223–225). Progesterone-mediated changes in T-cell gene expression have been associated with the development of TH2-type T-helper cell responses and with increased LIF expression (208,226). Because a shift in the intrauterine immune environment from TH2 to TH1 has been linked with early spontaneous pregnancy loss, the elevated intrauterine concentrations of progesterone characteristic of early pregnancy may promote an immune environment favoring pregnancy maintenance (199,208). To this point, in vitro evidence indicates that progesterone can inhibit mitogen-induced proliferation of and cytokine secretion by CD8+ T cells and can alter the expression of a transcription factor that drives the development of TH1 cells (227,228).
Levels of estrogen also rise dramatically during pregnancy, and attention has focused on the role of estrogen in immune modulation. A group of animal studies showed that estrogens improve immune responses in males after significant trauma and hemorrhage, suppress cell-mediated immunity after thermal injury, and protect against chronic renal allograft rejection (229–231). In vitro, estrogens appear to downregulate delayed-type hypersensitivity (DTH) reactions and promote the development of TH2-type immune responses, particularly at the elevated estrogen concentrations typical of pregnancy (232,233).