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      Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination

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          Abstract

          Lymphocyte proliferation, mobility and longevity make them prime targets for virus infection. Myeloid cells that process and present environmental antigens to lymphocytes are consequently an important line of defence. Subcapsular sinus macrophages (SSMs) filter the afferent lymph and communicate with B-cells. How they interact with B-cell-tropic viruses is unknown. We analysed their encounter with murid herpesvirus-4 (MuHV-4), an experimentally accessible gammaherpesvirus related to Kaposi's sarcoma-associated herpesvirus. MuHV-4 disseminated via lymph nodes, and intranasally or subcutaneously inoculated virions readily infected SSMs. However, this infection was poorly productive. SSM depletion with clodronate-loaded liposomes or with diphtheria toxin in CD169–diphtheria toxin receptor transgenic mice increased B-cell infection and hastened virus spread to the spleen. Dendritic cells provided the main route to B-cells, and SSMs slowed host colonization, apparently by absorbing virions non-productively from the afferent lymph.

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          Conditional gene targeting in macrophages and granulocytes using LysMcre mice.

          Conditional mutagenesis in mice has recently been made possible through the combination of gene targeting techniques and site-directed mutagenesis, using the bacteriophage P1-derived Cre/loxP recombination system. The versatility of this approach depends on the availability of mouse mutants in which the recombinase Cre is expressed in the appropriate cell lineages or tissues. Here we report the generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus. In double mutant mice harboring both the LysMcre allele and one of two different loxP-flanked target genes tested, a deletion efficiency of 83-98% was determined in mature macrophages and near 100% in granulocytes. Partial deletion (16%) could be detected in CD11c+ splenic dendritic cells which are closely related to the monocyte/macrophage lineage. In contrast, no significant deletion was observed in tail DNA or purified T and B cells. Taken together, LysMcre mice allow for both specific and highly efficient Cre-mediated deletion of loxP-flanked target genes in myeloid cells.
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            Notch–RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen

            Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch–RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8− DC subset and reduced the frequency of cytokine-secreting CD8− DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J–deficient splenic CD8− DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8− DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch–RBP-J signaling controls the maintenance of CD8− DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.
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              Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications.

              Selective depletion of macrophages from tissues in vivo can be used to investigate whether these cells are playing a role in defined biological processes. This question is particularly relevant to various host defense mechanisms. We have developed a macrophage 'suicide' technique, using the liposome mediated intracellular delivery of dichloromethylene-bisphosphonate (Cl2MBP or clodronate). The method is specific with respect to phagocytic cells of the mononuclear phagocyte system (MPS) for the following reasons: (1) The natural fate of liposomes is phagocytosis. (2) Once ingested by macrophages, the phospholipid bilayers of the liposomes are disrupted under the influence of lysosomal phospholipases. (3) Cl2MBP intracellularly released in this way does not easily escape from the cell by crossing the cell membranes. (4) Cl2MBP released in the circulation from dead macrophages or by leakage from liposomes, will not easily enter non-phagocytic cells and has an extremely short half life in the circulation and body fluids. In the present review, the preparation of Cl2MBP-liposomes has been described in detail. Furthermore, the mechanism of action of the new approach and its applicabilities are discussed.
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                Author and article information

                Journal
                J Gen Virol
                J. Gen. Virol
                JGV
                The Journal of General Virology
                Society for General Microbiology
                0022-1317
                1465-2099
                August 2015
                August 2015
                : 96
                : Pt 8
                : 2314-2327
                Affiliations
                [ 1]Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK
                [ 2]Sir Albert Sakzewski Virus Research Centre, Clinical Medical Virology Centre, School of Chemistry and Molecular Biosciences, Royal Children's Hospital and University of Queensland, Brisbane, Australia
                Author notes
                Correspondence Philip G. Stevenson p.stevenson@ 123456uq.edu.au
                Article
                000140
                10.1099/vir.0.000140
                4681069
                25872742
                acfd8183-4ddd-4071-8fe0-3c556260d928
                © 2015 The Authors

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/(.

                History
                : 08 March 2015
                : 07 April 2015
                Categories
                Standard
                Animal
                Large DNA Viruses
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                Microbiology & Virology
                Microbiology & Virology

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