Key Points
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Recent work in mice has revealed several mechanisms that either minimize the activation of maternal T cells with fetal or placental specificity, or minimize the possibility that such T cells, if activated, can harm the fetus.
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First, there is an absence of direct allorecognition of paternal MHC molecules expressed by cells of the conceptus.
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Second, dendritic cells are trapped within the decidua, thereby minimizing the immunogenic presentation of conceptus-derived antigens in the uterine draining lymph nodes.
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Third, regulatory T cells suppress T cell activation in response to conceptus-derived antigens.
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Fourth, epigenetic silencing of chemokine genes occurs in decidual stromal cells, which prevents activated T cells from accumulating at the maternal–fetal interface.
Abstract
Work on the mechanisms of fetomaternal tolerance has undergone a renaissance in recent years, and the general outlines of a solution to this long-standing paradox of 'transplantation' immunology have come into view. Here, we discuss several mechanisms, recently described in mice, that either minimize the activation of maternal T cells with fetal or placental specificity, or minimize the possibility that such T cells, if activated, are able to harm the fetus. The T cell response to antigens expressed by the conceptus serves as a paradigm for the study of tissue-specific immune tolerance and is relevant to the pathogenesis of immune-mediated pregnancy complications.
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Acknowledgements
Work in the author's laboratory has been supported by grants from the US National Institutes of Health, the American Cancer Society and the Leona M. and Harry B. Helmsley Charitable Trust. The author would like to thank the members of his laboratory for many stimulating discussions.
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Glossary
- Pre-eclampsia
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A disease specific to pregnancy that is triggered by placental dysfunction. It is characterized by diverse systemic symptoms, including hypertension and proteinuria. The incidence varies from 3% to 10% of pregnancies, and this disease is the leading cause of maternal mortality and fetal morbidity and mortality throughout the world.
- Immune privilege
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Immune-privileged sites are areas in the body with a decreased immune response to foreign antigens, including tissue grafts. Classic sites of immune privilege include the brain, eyes and testes.
- Haemochorial mode of placentation
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A form of placentation in which trophoblast cells erode the maternal vasculature, which results in the direct contact of maternal blood with trophoblasts.
- Decidua
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The specialized endometrial stromal tissue that encases the implanted conceptus. The decidua is predominantly comprised of decidual stromal cells, which differentiate from endometrial stromal cells following embryo implantation in the mouse. The decidua also contains various types of maternal leukocytes, and it makes direct contact with the trophoblasts on the outer surface of the conceptus to form the maternal–fetal interface.
- Trophoblasts
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The earliest extra-embryonic cells to differentiate from the cells of the mammalian embryo. They constitute the predominant cellular component of the placenta, surround the conceptus throughout gestation and make direct contact with maternal tissues.
- Minor histocompatibility antigens
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Polymorphic peptides derived from normal cellular proteins that can be recognized by T cells when presented on MHC molecules. Immune responses against these polymorphic antigens can result in graft-versus-host reactions, graft rejection or beneficial antitumour responses.
- Tetramer
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A reagent comprised of a fluorophore-conjugated core surrounded by four peptide—MHC complexes or ligand–CD1d complexes. In reality, these are much more than tetramers, because each of the four complexes involved comprises multiple components, and higher-order associations can also occur. Thus, 'oligomer' might be a more accurate term.
- Exosome
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A small lipid-bilayer vesicle that is released from activated cells following the fusion of a multivesicular body with the plasma membrane.
- Indoleamine 2,3-dioxygenase
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(IDO). An intracellular haem-containing enzyme that catalyses the oxidative catabolism of tryptophan. The activity of IDO reduces the availability of tryptophan, which can lead to T cell apoptosis and anergy.
- TC1 cells
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CD8+ cytotoxic T cells that produce T helper 1-type cytokines, particularly interferon-γ.
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Erlebacher, A. Mechanisms of T cell tolerance towards the allogeneic fetus. Nat Rev Immunol 13, 23–33 (2013). https://doi.org/10.1038/nri3361
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DOI: https://doi.org/10.1038/nri3361
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