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      Molecular definition of group 1 innate lymphoid cells in the mouse uterus

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          Abstract

          Determining the function of uterine lymphocytes is challenging because of the dynamic changes in response to sex hormones and, during pregnancy, to the invading foetal trophoblast cells. Here we provide a genome-wide transcriptome atlas of mouse uterine group 1 innate lymphoid cells (ILCs) at mid-gestation. Tissue-resident Eomes +CD49a + NK cells (trNK), which resemble human uterine NK cells, are most abundant during early pregnancy, and have gene signatures associated with TGF-β responses and interactions with trophoblast, epithelial, endothelial, smooth muscle cells, leucocytes and extracellular matrix. Conventional NK cells expand late in gestation and may engage in crosstalk with trNK cells involving IL-18 and IFN-γ. Eomes CD49a + ILC1s dominate before puberty, and specifically expand in second pregnancies when the expression of the memory cell marker CXCR6 is upregulated. These results identify trNK cells as the cellular hub of uterine group 1 ILCs, and mark CXCR6 + ILC1s as potential memory cells of pregnancy.

          Abstract

          Studying the uterine lymphocyte pool is difficult due to its dynamic nature induced by various pregnancy-related factors. Here the authors provide, using transcriptome data from sorted mouse group 1 innate lymphoid cells (ILC), a molecular atlas of these cells, which implicates tissue-resident natural killer cells as a hub for uterine immune crosstalk.

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          De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells.

          Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates TH17 cell-mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell-mediated inflammatory diseases.
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            Transcriptional Programs Define Molecular Characteristics of Innate Lymphoid Cell Classes and Subsets

            The diversity of innate lymphoid cells (ILCs) is rapidly expanding. Three ILC classes have emerged, ILC1, ILC2, and ILC3, with ILC1 and ILC3 including several subsets. The classification of some subsets is unclear and it remains controversial whether NK cells and ILC1 are distinct cell types. To address these issues, we analyzed ILCs and NK cells gene expression within mouse small intestine, spleen, and liver, as part of the Immunological Genome Project. Results identify unique gene-expression patterns for some ILCs and overlapping patterns between ILC1 and NK cells, whereas few ILC subsets remain indistinguishable. A transcriptional program shared by small intestine ILCs and a core ILC signature is identified. Transcripts that suggest novel ILC functions and developmental paths are revealed and discussed.
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              Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success

              Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.
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                Author and article information

                Contributors
                fc287@medschl.cam.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                29 October 2018
                29 October 2018
                2018
                : 9
                : 4492
                Affiliations
                [1 ]GRID grid.454369.9, Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, , NIHR Cambridge Biomedical Research Centre, ; Cambridge, CB2 0SW UK
                [2 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Physiology, Development and Neuroscience, , University of Cambridge, ; Cambridge, CB2 3EG UK
                [3 ]ISNI 0000000121885934, GRID grid.5335.0, Centre for Trophoblast Research, , University of Cambridge, ; Cambridge, CB2 3EG UK
                [4 ]ISNI 0000 0004 1760 0109, GRID grid.419504.d, G. Gaslini Institute, Genoa, ; 16147 Genoa, Italy
                [5 ]Policlinico San Martino IRCCS per l’Oncologia, Genoa, 16132 Genova, Italy
                [6 ]ISNI 0000 0001 2151 3065, GRID grid.5606.5, Department of Experimental Medicine (DIMES), , University of Genoa, ; 16132 Genova, Italy
                [7 ]ISNI 0000 0001 0727 6809, GRID grid.414125.7, Department of Immunology, , IRCCS Bambino Gesù Children’s Hospital, ; 00165 Rome, Italy
                [8 ]ISNI 0000 0001 2151 3065, GRID grid.5606.5, Center of Excellence for Biomedical Research (CEBR), , University of Genova, ; 16132 Genova, Italy
                [9 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Pathology, , University of Cambridge, ; Cambridge, CB2 1QP UK
                [10 ]ISNI 0000 0004 0626 1500, GRID grid.463905.d, Present Address: Innate Pharma Research Labs, Innate Pharma, ; 13009 Marseille, France
                [11 ]ISNI 0000 0001 2353 6535, GRID grid.428999.7, Present Address: Department of Immunology, , Pasteur Institute, ; 75015 Paris, France
                Author information
                http://orcid.org/0000-0002-8166-5500
                http://orcid.org/0000-0002-9097-5869
                http://orcid.org/0000-0002-0598-3793
                http://orcid.org/0000-0001-9179-0447
                http://orcid.org/0000-0002-5072-7748
                http://orcid.org/0000-0003-4658-1747
                Article
                6918
                10.1038/s41467-018-06918-3
                6206068
                30374017
                dafcdcac-f1a4-4698-869b-73536cc0427e
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 24 May 2018
                : 26 September 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 200841/Z/16/Z
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research);
                Award ID: 9962, 19920, 15283
                Award Recipient :
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