The placenta may also inhibit the mother’s T cells by an active mechanism of nutrient depletion. The enzyme indoleamine 2,3-dioxygenase (IDO) is expressed at a high level by cells at the maternal–fetal interface. This enzyme depletes the essential amino acid tryptophan at this site, and T cells starved of tryptophan show reduced responsiveness. Inhibition of IDO in pregnant mice, using the inhibitor 1-methyltryptophan, causes rapid rejection of allogeneic, but not syngeneic, fetuses.
The cytokine milieu at the maternal–fetal interface also contributes to fetal tolerance. Both the uterine epithelium and the trophoblast secrete TGF-β and IL-10. This combination of cytokines suppresses the development of effector T cells in favor of iTreg cells (see Section 9-23). Regulatory T cells are increased during pregnancy, including iTreg cells in the placenta. These cells are important for suppressing responses to the fetus in mice, as iTreg deficiency promotes fetal resorption—the equivalent of spontaneous abortion in humans—as does induction of TH1-inducing cytokines (for example, IFN-γ and IL-12). Provocatively, a regulatory element that controls FoxP3 expression in iTreg
Fig. 15.56 The fetus is an allograft that is not rejected. With very few exceptions, the mother and father in human families have different HLA types (top panel). When the mother becomes pregnant she carries for 9 months a fetus that expresses one HLA haplotype of maternal origin (pink) and one HLA haplotype of paternal origin (blue) (bottom panel). Although the paternal HLA class I and II molecules expressed by the fetus are alloantigens against which the mother’s immune system has the potential to respond, the fetus does not provoke such a response during pregnancy and is protected from preexisting alloreactive antibodies or T cells. Even when the mother bears several children to the same father, no sign of immunological rejection is seen.
cells, but is not required for FoxP3 expression by nTreg cells, has been found only in placental mammals. This suggests that iTreg cells might have evolved to play an important role in maternal–fetal tolerance. Finally, stromal cells of the specialized maternal uterine tissue that directly interfaces with the placenta— the decidua—appear to repress the local expression of key T cell-attracting chemokines. Collectively, then, both maternal and fetal factors contribute to the formation of an immunologically privileged site akin to other sites of local immune suppression that allow prolonged acceptance of tissue grafts, such as the eye (see Section 15-5).
Summary.
Clinical transplantation is now an everyday reality, its success built on MHC matching, immunosuppressive drugs, and advances in surgical techniques. However, even accurate MHC matching does not prevent graft rejection; other genetic differences between host and donor can result in allogeneic proteins whose peptides are presented by MHC molecules on the grafted tissue, and responses to these can lead to rejection. Because we lack the ability to specifically suppress the response to the graft without compromising host defense, most transplants require generalized immunosuppression of the recipient that can increase the risk of cancer and infection. The fetus is a natural allograft that must be accepted for the species to survive. A better understanding of tolerance to the fetus could ultimately provide insights for inducing specific allograft tolerance in transplantation.
Summary to Chapter 15.