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      Immune cell subset differentiation and tissue inflammation

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          Abstract

          Immune cells were traditionally considered as major pro-inflammatory contributors. Recent advances in molecular immunology prove that immune cell lineages are composed of different subsets capable of a vast array of specialized functions. These immune cell subsets share distinct duties in regulating innate and adaptive immune functions and contribute to both immune activation and immune suppression responses in peripheral tissue. Here, we summarized current understanding of the different subsets of major immune cells, including T cells, B cells, dendritic cells, monocytes, and macrophages. We highlighted molecular characterization, frequency, and tissue distribution of these immune cell subsets in human and mice. In addition, we described specific cytokine production, molecular signaling, biological functions, and tissue population changes of these immune cell subsets in both cardiovascular diseases and cancers. Finally, we presented a working model of the differentiation of inflammatory mononuclear cells, their interaction with endothelial cells, and their contribution to tissue inflammation. In summary, this review offers an updated and comprehensive guideline for immune cell development and subset differentiation, including subset characterization, signaling, modulation, and disease associations. We propose that immune cell subset differentiation and its complex interaction within the internal biological milieu compose a “pathophysiological network,” an interactive cross-talking complex, which plays a critical role in the development of inflammatory diseases and cancers.

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          Most cited references137

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          Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.

          Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8alpha+ dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8alpha+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3-/- mice were defective in cross-presentation, and Batf3-/- mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3-/- mice. These results suggest an important role for CD8alpha+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.
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            Mechanisms of resistance to immune checkpoint inhibitors

            Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors (‘targeted therapies’) largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, durable responses suggestive of long-lasting immunologic memory are commonly seen in large subsets of patients treated with ICI. However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease. In addition, late relapses are now emerging with longer follow-up of clinical trial populations, suggesting the emergence of acquired resistance. As robust biomarkers to predict clinical response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clinical studies and correlative clinical data. Improved understanding of molecular and immunologic mechanisms of ICI response (and resistance) may not only identify novel predictive and/or prognostic biomarkers, but also ultimately guide optimal combination/sequencing of ICI therapy in the clinic. Here we review the emerging clinical and pre-clinical data identifying novel mechanisms of innate and acquired resistance to immune checkpoint inhibition.
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              IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses.

              Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (T(H)1)-T(H)17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.
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                Author and article information

                Contributors
                215-707-5986 , hongw@temple.edu
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                31 July 2018
                31 July 2018
                2018
                : 11
                : 97
                Affiliations
                [1 ]ISNI 0000 0001 2248 3398, GRID grid.264727.2, Center for Metabolic Disease Research, Lewis Kats School of Medicine, , Temple University, ; Medical Education and Research Building, Room 1060, 3500 N. Broad Street, Philadelphia, PA 19140 USA
                [2 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Pathology and Laboratory Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [3 ]ISNI 0000 0001 2248 3398, GRID grid.264727.2, Department of Pharmacology, Lewis Kats School of Medicine, , Temple University, ; Philadelphia, PA USA
                [4 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Cardiovascular Medicine Department, Sun Yat-Sen Memorial Hospital, , Sun Yat-Sen University, ; Guangzhou, 510120 China
                [5 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Key Laboratory of Cardiovascular Disease and Molecular Intervention, , Nanjing Medical University, ; Nanjing, China
                Author information
                http://orcid.org/0000-0001-6258-4070
                Article
                637
                10.1186/s13045-018-0637-x
                6069866
                30064449
                58ba0b22-93c2-41d2-8025-c6d5b52ce8e7
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 May 2018
                : 2 July 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: HL117654
                Award ID: HL-110764
                Award ID: HL130233
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: HL131460
                Award ID: DK104116
                Award ID: DK113775
                Award ID: HL132399
                Award ID: HL138749
                Award ID: 5T32DK007780
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000968, American Heart Association;
                Award ID: 17SDG33671051
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                immune cell subset differentiation,t cell,b cell,dendritic cell,monocyte,macrophage,cardiovascular disease,cancer

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