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      Local immune recognition of trophoblast in early human pregnancy: controversies and questions

      review-article
      1 , , 2
      Nature Reviews. Immunology
      Nature Publishing Group UK
      NK cells, Reproductive biology

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          Abstract

          The role of the maternal immune system in reproductive success in humans remains controversial. Here we focus on the events that occur in the maternal decidua during the first few weeks of human pregnancy, because this is the site at which maternal leukocytes initially interact with and can recognize fetal trophoblast cells, potentially involving allorecognition by both T cells and natural killer (NK) cells. NK cells are the dominant leukocyte population in first-trimester decidua, and genetic studies point to a role of allorecognition by uterine NK cells in establishing a boundary between the mother and the fetus. By contrast, definitive evidence that allorecognition by decidual T cells occurs during the first trimester is lacking. Thus, our view is that during the crucial period when the placenta is established, damaging T cell-mediated adaptive immune responses towards placental trophoblast are minimized, whereas NK cell allorecognition contributes to successful implantation and healthy pregnancy.

          Abstract

          Major human pregnancy disorders arise from the failure of placental trophoblast to access sufficient supplies of maternal oxygen and nutrients. Key to understanding this process are the interactions that occur early in pregnancy between trophoblast cells that invade the decidua and maternal uterine immune cells.

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          Transforming Growth Factor-β Signaling in Immunity and Cancer

          Transforming growth factor (TGF)-β is a crucial enforcer of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Perturbations in TGF-β signaling underlie inflammatory diseases and promote tumor emergence. TGF-β is also central to immune suppression within the tumor microenvironment, and recent studies have revealed roles in tumor immune evasion and poor responses to cancer immunotherapy. Here, we present an overview of the complex biology of the TGF-β family and its context-dependent nature. Then, focusing on cancer, we discuss the roles of TGF-β signaling in distinct immune cell types and how this knowledge is being leveraged to unleash the immune system against the tumor.
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            Single-cell reconstruction of the early maternal–fetal interface in humans

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              A function for interleukin 2 in Foxp3-expressing regulatory T cells.

              Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.
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                Author and article information

                Contributors
                am485@cam.ac.uk
                Journal
                Nat Rev Immunol
                Nat Rev Immunol
                Nature Reviews. Immunology
                Nature Publishing Group UK (London )
                1474-1733
                1474-1741
                3 October 2022
                : 1-14
                Affiliations
                [1 ]GRID grid.5335.0, ISNI 0000000121885934, Department of Pathology, , University of Cambridge, ; Cambridge, UK
                [2 ]GRID grid.5335.0, ISNI 0000000121885934, Department of Obstetrics and Gynaecology, , University of Cambridge, ; Cambridge, UK
                Author information
                http://orcid.org/0000-0002-8388-9073
                Article
                777
                10.1038/s41577-022-00777-2
                9527719
                36192648
                43b6ed6e-b70c-4849-8bc5-9b7859b0df6b
                © Springer Nature Limited 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 23 August 2022
                Categories
                Review Article

                nk cells,reproductive biology
                nk cells, reproductive biology

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