T-helper (Th) cells play a central role in modulating immune responses. The Th1/Th2 paradigm has now developed into the new Th1/Th2/Th17 paradigm. In addition to effector cells, Th cells are regulated by regulatory T (Treg) cells. Their capacity to produce cytokines is suppressed by immunoregulatory cytokines such as transforming growth factor (TGF)-beta and interleukin (IL)-10 or by cell-to-cell interaction. Here, we will review the immunological environment in normal pregnancy and complicated pregnancy, such as implantation failure, abortion, preterm labor, and preeclampsia from the viewpoint of the new Th1/Th2/Th17 and Treg paradigms.

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Th1/Th2/Th17 and Regulatory T-Cell Paradigm in Pregnancy

The traditional way to study the immunology of pregnancy follows the classical transplantation model, which views the fetus as an allograft. A more recent approach, which is the subject of this Review, focuses on the unique, local uterine immune response to the implanting placenta. This approach requires knowledge of placental structure and its variations in different species, as this greatly affects the type of immune response that is generated by the mother. At the implantation site, cells from the mother and the fetus intermingle during pregnancy. Unravelling what happens here is crucial to our understanding of why some human pregnancies are successful whereas others are not.

Immunology of placentation in eutherian mammals.

The immune cells that reside at the interface between the placenta and uterus are thought to play many important roles in pregnancy. Recent work has revealed that the composition and function of these cells are locally controlled by the specialized uterine stroma (the decidua) that surrounds the implanted conceptus. Here, I discuss how key immune cell types (natural killer cells, macrophages, dendritic cells, and T cells) are either enriched or excluded from the decidua, how their function is regulated within the decidua, and how they variously contribute to pregnancy success or failure. The discussion emphasizes the relationship between human and mouse studies. Deeper understanding of the immunology of the maternal-fetal interface promises to yield significant insight into the pathogenesis of many human pregnancy complications, including preeclampsia, intrauterine growth restriction, spontaneous abortion, preterm birth, and congenital infection.

Immunology of the Maternal-Fetal Interface

The comparison of the immunological state of pregnancy to an immunosuppressed host-graft model continues to lead research and clinical practice to ill-defined approaches. This Review discusses recent evidence that supports the idea that immunological responses at the receptive maternal-fetal interface are not simply suppressed but are instead highly dynamic. We discuss the crucial role of trophoblast cells in shaping not only the way in which immune cells respond to the invading blastocyst but also how they collectively react to external stimuli. We also discuss the role of the microbiota in promoting a tolerogenic maternal immune system and highlight how subclinical viral infections can disrupt this status quo, leading to pregnancy complications.

The unique immunological and microbial aspects of pregnancy

The evolutionary adaptation in mammals that allows implantation of their embryos in the mother's womb creates an immunological problem. Although it ensures optimal nourishment and protection of the fetus throughout its early development, intimate contact with the mother's uterine tissue makes the fetus a potential target for her immune system. As half the fetal genes are derived from the father, the developing embryo and placenta must be considered a 'semi-allograft'. Such a mismatched organ transplant would be readily rejected without powerful immune suppression. During pregnancy, however, the semi-allogeneic fetus is protected from assault by the maternal immune system over an extended period of time. The mother's immune system seems to recognize the fetus as 'temporary self'. How this feat is managed is key to understanding immunological tolerance and intervention in treating disease.

Mother's little helpers: mechanisms of maternal-fetal tolerance

Human pregnancy represents a situation of semiallograft to maternal host. Therefore, it has been reported that tolerance to the fetal allograft represents a mechanism for maintaining a pregnancy. CD4 + CD25 bright regulatory T cells are known to play an important role in the development and maintenance of tolerance in peripheral tissues. However, the potential role of CD4 + CD25 bright T cells in maintaining human pregnancy has not been reported. In this study, we show that early human pregnancy decidua contains an abundance of CD4 + CD25 bright T cells, which express CD152(CTLA-4) at a high level. CD4 + CD25 bright T cells mediate potent inhibition of autologous T-cell proliferation by anti-CD3 stimulation. Furthermore, these cells inhibit the proliferation of autologous CD4 + CD25 - T cells in a dose-dependent fashion. This suppressive function of decidual CD4 + CD25 + T cells required cell-to-cell contact. The proportion of decidual CD4 + CD25 bright T cells was significantly lower in specimens from spontaneous abortion compared to those from specimens from induced abortions. These results suggest that decidual CD4 + CD25 bright T cells contribute to the mechanisms mediating maternal immune tolerance of conceptus antigens and therefore might contribute to the maintenance of pregnancy.

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S. Higuma

Papers

Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases.