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      Defining trained immunity and its role in health and disease

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          Abstract

          Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed ‘trained immunity’, a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define ‘trained immunity’ as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.

          Abstract

          Here a group of leaders in the field define our current understanding of ‘trained immunity’, which refers to the memory-type responses that occur in the innate immune system. The authors discuss our current understanding of the key epigenetic and metabolic processes involved in trained immunity and consider its relevance in immune-mediated diseases and cancer.

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          Most cited references127

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          Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.

          Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naïve, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans. Copyright © 2014, American Association for the Advancement of Science.
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            NK cell recognition.

            The integrated processing of signals transduced by activating and inhibitory cell surface receptors regulates NK cell effector functions. Here, I review the structure, function, and ligand specificity of the receptors responsible for NK cell recognition.
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              Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.

              Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
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                Author and article information

                Contributors
                Mihai.Netea@radboudumc.nl
                eicke.latz@uni-bonn.de
                Journal
                Nat Rev Immunol
                Nat. Rev. Immunol
                Nature Reviews. Immunology
                Nature Publishing Group UK (London )
                1474-1733
                1474-1741
                4 March 2020
                : 1-14
                Affiliations
                [1 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Internal Medicine and Radboud Center for Infectious Diseases, , Radboud University Medical Center, ; Nijmegen, Netherlands
                [2 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Radboud Institute for Molecular Life Sciences, , Radboud University Medical Center, ; Nijmegen, Netherlands
                [3 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Department of Genomics and Immunoregulation, Life and Medical Sciences Institute, , University of Bonn, ; Bonn, Germany
                [4 ]ISNI 0000 0001 2173 6322, GRID grid.411418.9, Department of Genetics, , CHU Sainte-Justine Research Centre, ; Montreal, QC Canada
                [5 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Department of Pediatrics, , University of Montreal, ; Montreal, QC Canada
                [6 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Genetics Section, Department of Medicine, , The University of Chicago, ; Chicago, IL USA
                [7 ]ISNI 0000 0001 1091 2917, GRID grid.412282.f, Institute for Clinical Chemistry and Laboratory Medicine, , University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, ; Dresden, Germany
                [8 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Cardiovascular Science, Queen’s Medical Research Institute, , University of Edinburgh, ; Edinburgh, UK
                [9 ]ISNI 0000 0000 9064 4811, GRID grid.63984.30, Meakins-Christie Laboratories, Department of Medicine, , McGill University Health Centre, ; Montreal, QC Canada
                [10 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Department of Microbiology and Immunology, , McGill University, ; Montreal, QC Canada
                [11 ]ISNI 0000 0000 9064 4811, GRID grid.63984.30, McGill International TB Centre, , McGill University Health Centre, ; Montreal, QC Canada
                [12 ]ISNI 0000 0001 2166 1519, GRID grid.134907.8, Howard Hughes Medical Institute, Robin Chemers Laboratory of Mammalian Cell Biology and Development, , The Rockefeller University, ; New York, NY USA
                [13 ]ISNI 0000 0004 1937 1151, GRID grid.7836.a, Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, , University of Cape Town, ; Cape Town, South Africa
                [14 ]ISNI 0000 0001 2181 4263, GRID grid.9983.b, Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, , Faculdade de Medicina Universidade de Lisboa, ; Lisbon, Portugal
                [15 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Translational and Molecular Imaging Institute, Department of Radiology, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [16 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Oncological Sciences, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [17 ]ISNI 0000 0004 0398 8763, GRID grid.6852.9, Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, , Eindhoven University of Technology, ; Eindhoven, Netherlands
                [18 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Myeloid Cell Biology, Life and Medical Sciences Institute, , University of Bonn, ; Bonn, Germany
                [19 ]ISNI 0000 0001 0728 0170, GRID grid.10825.3e, Bandim Health Project, OPEN, Department of Clinical Research, , University of Southern Denmark, ; Odense, Denmark
                [20 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, Immunology Program, , Memorial Sloan Kettering Cancer Center, ; New York, NY USA
                [21 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, , Memorial Sloan Kettering Cancer Center, ; New York, NY USA
                [22 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Immunology and Microbial Pathogenesis, , Weill Cornell Medical College, ; New York, NY USA
                [23 ]GRID grid.66859.34, Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [24 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Center for Computational and Integrative Biology, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA USA
                [25 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Institute of Innate Immunity, , University Hospital, University of Bonn, ; Bonn, Germany
                [26 ]ISNI 0000 0001 0742 0364, GRID grid.168645.8, Division of Infectious Diseases and Immunology, , University of Massachusetts Medical School, ; Worcester, MA USA
                [27 ]ISNI 0000 0004 0438 0426, GRID grid.424247.3, German Center for Neurodegenerative Diseases, ; Bonn, Germany
                Author information
                http://orcid.org/0000-0003-2421-6052
                Article
                285
                10.1038/s41577-020-0285-6
                7186935
                32132681
                5b41110c-9e50-4a0d-9a11-eac37f309e91
                © Springer Nature Limited 2020

                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
                : 24 January 2020
                Categories
                Review Article

                infection,vaccines,immunotherapy,sars-cov-2
                infection, vaccines, immunotherapy, sars-cov-2

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