The activity of specific suppressive immune cells, some of which persist to aid subsequent pregnancies, helps to explain how a pregnant female's immune system tolerates fetal antigens inherited from the father. See Letter p.102
Pregnancy poses a conundrum for the immune systems of placental mammals. A pregnant female's immune system has to defend both mother and fetus from pathogens, while at the same time tolerating the fetus, which contains antigens that the maternal immune system recognizes as foreign because they are the products of genes inherited from the father. On page 102 of this issue, Rowe et al.1 demonstrate that, during pregnancy, immune cells called regulatory T cells that recognize these paternal antigens proliferate in the mother and specifically suppress the maternal immune response against the fetus. Furthermore, the authors show that a pool of these cells remains long after delivery, facilitating tolerance in subsequent pregnancies. The description of this mechanism may, in the future, help to develop treatments for pre-eclampsia and prevent miscarriages resulting from immune rejection of the fetus2.
Genetically, a fetus is half mother, half father. From an evolutionary perspective, maternal exposure to paternal antigens in the fetus is a relatively new problem: most animals lay eggs, so tolerance is not an issue. Yet physical attachment of the developing mammalian fetus to the mother's uterine wall by the placenta provides clear benefits — it allows gas exchange, nutrient uptake and waste disposal through the mother's blood circulation, providing optimal conditions for the growth of the developing fetus. A systemic immune suppression to facilitate this fetal 'implantation' would be much too risky because it would expose the mother and developing offspring to infection. So placental animals had to evolve a mechanism for localized and specific immune suppression.
Rowe and colleagues have helped to clarify this mechanism. It was previously known that the mother's immune system tolerates the fetus despite being fully aware of it3 and that a class of immune cell called regulatory T cells has a key role in this process4. Regulatory T cells act as suppressors of immune responses5; they are best known for their role in the prevention of autoimmune responses, but they are also involved in other functions, such as shutting down immune responses after successful elimination of a pathogen. These cells differentiate from precursor T cells in response to expression of just a single protein, Foxp3 (ref. 5), either in the thymus during T-cell development (thymic regulatory T cells) or in peripheral immune organs, such as the spleen or lymph nodes, during immune responses (induced regulatory T cells).
To assess how regulatory T cells promote immune tolerance of a fetus, Rowe et al. studied the fate of antigen-specific T cells responding to the antigen when encountering it either as a pathogen antigen or as a paternally derived antigen during pregnancy. When the authors infected mice with Listeria bacteria expressing the antigen, they observed antigen-specific 'helper' T cells proliferating — the expected immune response to a foreign antigen. But the immune response they saw in pregnant mice when the same antigen was expressed by the fetus was characterized by a substantial expansion in the number of maternal antigen-specific regulatory T cells (Fig. 1). This was the result of both proliferation of antigen-specific thymic regulatory T cells, and the conversion of antigen-specific helper T cells in peripheral organs to regulatory T cells through the induction of Foxp3. The authors show that this immune suppression is highly antigen-specific, which explains why the pregnant female's ability to launch immune responses against infections is not affected.
These results demonstrate that the context of pregnancy can determine whether a foreign antigen is attacked or tolerated. The crucial role of regulatory T cells in this process provokes the question of whether these cells might have influenced the evolution of placental implantation of the fetus. Two recent comparative-genomics studies6,7 provide some clues. Although a Foxp3-like gene is present in fish, the protein it encodes lacks key domains required for the commitment of T cells to the regulatory lineage and for their function6. Intriguingly, it seems that Foxp3 was lost from the genome of birds, but retained in mammals, in which it acquired additional functional domains6 and additional elements that regulate its expression7. Foxp3 in monotremes (egg-laying mammals) contains most, if not all, of the functional domains6, which indicates that regulatory T cells evolved before the evolution of fetal implantation. Thus, it is tempting to speculate that the evolutionary gain of these cells facilitated the evolution of invasive placentation, because it provided the maternal immune system with a mechanism to tolerate the fetus without unduly compromising its responsiveness to pathogens.
Intriguingly, Rowe et al. also show that the number of fetal-antigen-specific regulatory T cells persists at elevated levels long after delivery of the baby, and that the cells rapidly proliferate during subsequent pregnancies (Fig. 1). This is reminiscent of the regulatory T-cell 'memory' that is seen for some self-antigens and that helps to prevent autoimmunity8. These fetus-specific memory cells might explain why pre-eclampsia (a condition associated with impaired maternal immune tolerance of the fetus) is predominantly a disease of the first pregnancy unless there is a change in father.
The generation of regulatory T-cell memory towards fetal antigens is part of a broader change in the immunological status quo that is triggered by pregnancy. For example, some autoimmune diseases, such as arthritis, are temporarily ameliorated, and regulatory T cells have been shown to be responsible for this beneficial effect9. Unfortunately, the diseases return with a vengeance after delivery and do not seem to benefit from the generation of protective regulatory T-cell memory. However, studies building on Rowe and colleagues' report of regulatory T-cell persistence following pregnancy may in the future help to harness elements of this process for the treatment of autoimmune disease.
Rowe, J., Ertelt, J., Xin, L. & Way, S. S. Nature 490, 102–106 (2012).
Sasaki, Y. Mol. Hum. Reprod. 10, 347–353 (2004).
Tafuri, A., Alferink, J., Möller, P., Hämmerling, G. J. & Arnold, B. Science 270, 630–633 (1995).
Aluvihare, V. R., Kallikourdis, M. & Betz, A. G. Nature Immunol. 5, 266–271 (2004).
Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. Nature Rev. Immunol. 10, 490–500 (2010).
Andersen, K. G., Nissen, J. K. & Betz, A. G. Front. Immunol. 3, 113 (2012).
Samstein, R. M., Josefowicz, S. Z., Arvey, A., Treuting, P. M. & Rudensky, A. Y. Cell 150, 29–38 (2012).
Rosenblum, M. D. et al. Nature 480, 538–542 (2011).
Munoz-Suano, A., Kallikourdis, M., Sarris, M. & Betz, A. G. J. Autoimmunity 38, J103–J108 (2012).
About this article
The American Journal of Dermatopathology (2019)
Mechanism and Antiviral Therapy in Preventing Mother-to-Child Transmission During Pregnancy with Hepatitis B Virus Infection
Hepatitis Monthly (2019)
Chronic inflammatory lesions of the placenta are associated with an up-regulation of amniotic fluid CXCR3: A marker of allograft rejection
Journal of Perinatal Medicine (2018)
Inhibition of pregnancy-associated granulocytic myeloid-derived suppressor cell expansion and arginase-1 production in preeclampsia
Journal of Reproductive Immunology (2018)
Journal of Perinatal Medicine (2017)