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      Unique Eomes + NK Cell Subsets Are Present in Uterus and Decidua During Early Pregnancy

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          Abstract

          Decidual and uterine natural killer (NK) cells have been shown to contribute to the successful pregnancy both in humans and mice. NK cells represent “cytotoxic” group 1 innate lymphoid cells (ILCs) and are distinct from the recently described “helper” ILC1. Here, we show that both in humans and mice the majority of group 1 ILC in endometrium/uterus and decidua express Eomesodermin (Eomes), thus suggesting that they are developmentally related to conventional NK cells. However, they differ from peripheral NK cells. In humans, Eomes + decidual NK (dNK) cells express CD49a and other markers of tissue residency, including CD103, integrin β7, CD9, and CD69. The expression of CD103 allows the identification of different subsets of IFNγ-producing Eomes + NK cells. We show that TGFβ can sustain/induce CD103 and CD9 expression in dNK cells and decidual CD34-derived NK cells, indicating that the decidual microenvironment can instruct the phenotype of Eomes + NK cells. In murine decidua and uterus, Eomes + cells include CD49a CD49b + conventional NK cells and CD49a + cells. Notably, Eomes +CD49a + cells are absent in spleen and liver. Decidual and uterine Eomes +CD49a + cells can be dissected in two peculiar cell subsets according to CD49b expression. CD49a +CD49b and CD49a +CD49b + cells are enriched in immature CD11b lowCD27 high cells, while CD49a CD49b + cells contain higher percentages of mature CD11b highCD27 low cells, both in uterus and decidua. Moreover, Eomes +CD49a +CD49b cells decrease during gestation, thus suggesting that this peculiar subset may be required in early pregnancy rather than on later phases. Conversely, a minor Eomes CD49a + ILC1 population present in decidua and uterus increases during pregnancy. CD49b Eomes ± cells produce mainly TNF, while CD49a CD49b + conventional NK cells and CD49a +CD49b + cells produce both IFNγ and TNF. Thus, human and murine decidua contains unique subsets of group 1 ILCs, including Eomes + and Eomes cells, with peculiar phenotypic and functional features. Our study contributes to re-examination of the complexity of uterine and decidual ILC subsets in humans and mice and highlights the role of the decidual microenvironment in shaping the features of these cells.

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          Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy.

          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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            Maturation of mouse NK cells is a 4-stage developmental program.

            Surface density of CD27 and CD11b subdivides mouse natural killer (NK) cells into 4 subsets: CD11b(low)CD27(low), CD11b(low)CD27(high), CD11b(high)CD27(high), and CD11b(high)CD27(low). To determine the developmental relationship between these 4 subsets, we used several complementary approaches. First, we took advantage of NDE transgenic mice that express enhanced green fluorescent protein (EGFP) and diphtheria toxin receptor specifically in NK cells. Diphtheria toxin injection leads to a transient depletion of NK cells, allowing the monitoring of the phenotype of developing EGFP+ NK cells after diphtheria toxin injection. Second, we evaluated the overall proximity between NK-cell subsets based on their global gene profile. Third, we compared the proliferative capacity of NK-cell subsets at steady state or during replenishment of the NK-cell pool. Fourth, we performed adoptive transfers of EGFP+ NK cell subsets from NDE mice into unirradiated mice and followed the fate of transferred cells. The results of these various experiments collectively support a 4-stage model of NK-cell maturation CD11b(low)CD27(low) --> CD11b(low)CD27(high) --> CD11b(high)CD27(high) --> CD11b(high)CD27(low). This developmental program appears to be associated with a progressive acquisition of NK-cell effector functions.
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              Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells.

              The surface density of the triggering receptors responsible for the natural killer (NK)-mediated cytotoxicity is crucial for the ability of NK cells to kill susceptible target cells. In this study, we show that transforming growth factor beta1 (TGFbeta1) down-regulates the surface expression of NKp30 and in part of NKG2D but not that of other triggering receptors such as NKp46. The TGFbeta1-mediated inhibition of NKp30 surface expression reflects gene regulation at the transcriptional level. NKp30 has been shown to represent the major receptor involved in the NK-mediated killing of dendritic cells. Accordingly, the TGFbeta1-dependent down-regulation of NKp30 expression profoundly inhibited the NK-mediated killing of dendritic cells. On the contrary, killing of different NK-susceptible tumor cell lines was variably affected, reflecting the differential usage of NKp30 and/or NKG2D in the lysis of such tumors. Our present data suggest a possible mechanism by which TGFbeta1-producing dendritic cells may acquire resistance to the NK-mediated attack.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                07 January 2016
                2015
                : 6
                : 646
                Affiliations
                [1] 1G. Gaslini Institute , Genoa, Italy
                [2] 2Department of Experimental Medicine (DIMES), Università degli Studi di Genova , Genoa, Italy
                [3] 3IRCCS AOU San Martino-IST , Genoa, Italy
                [4] 4Department of Neurosciences Rehabilitation Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), Università degli Studi di Genova , Genoa, Italy
                [5] 5CIRI, Centre International de Recherche en Infectiologie – INSERM, Ecole Normale Supérieure de Lyon, Université Lyon 1 , CNRS, Lyon, France
                [6] 6Department of Immunology, IRCCS Bambino Gesù Children’s Hospital , Rome, Italy
                Author notes

                Edited by: Joseph C. Sun, Memorial Sloan-Kettering Cancer Center, USA

                Reviewed by: Roland Jacobs, Hannover Medical University, Germany; Jacques Zimmer, Luxembourg Institute of Health (LIH), Luxembourg

                *Correspondence: Paola Vacca, paola.vacca@ 123456yahoo.it ; Lorenzo Moretta, lorenzo.moretta@ 123456opbg.net

                Elisa Montaldo, Paola Vacca and Laura Chiossone have contributed equally to this work.

                Specialty section: This article was submitted to NK Cell Biology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2015.00646
                4794975
                27004067
                1479f599-1f2d-46c3-af08-c7441503d9ce
                Copyright © 2016 Montaldo, Vacca, Chiossone, Croxatto, Loiacono, Martini, Ferrero, Walzer, Moretta and Mingari.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 October 2015
                : 11 December 2015
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 37, Pages: 11, Words: 6652
                Funding
                Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010
                Award ID: IG2010 project n.10225, IG2014 project n.15283, Special Program Molecular Clinical Oncology 5x1000 project n.9962
                Funded by: Ministero della Salute 10.13039/501100003196
                Award ID: RO strategici 8/07
                Funded by: Università degli Studi di Genova 10.13039/501100004702
                Award ID: Progetto Ateneo 2013
                Categories
                Immunology
                Original Research

                Immunology
                ilc,nk cells,ilc1,eomes,pregnancy,tissue-resident nk cells
                Immunology
                ilc, nk cells, ilc1, eomes, pregnancy, tissue-resident nk cells

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