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      Ablation of CD8α + dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice

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          Abstract

          Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization. Ldlr −/− mice were transplanted with batf3 −/− or wt bone marrow and put on a western type diet. Hematopoietic batf3 deficiency sharply decreased CD8α + DC numbers in spleen and lymph nodes (>80%; P < 0,001). Concordantly, batf3 −/− chimeras had a 75% reduction in OT-I cross-priming capacity in vivo. Batf3 −/− chimeric mice did not show lower Tcell or other leukocyte subset numbers. Despite dampened cross-presentation capacity, batf3 −/− chimeras had equal atherosclerosis burden in aortic arch and root. Likewise, batf3 −/− chimeras and wt mice revealed no differences in parameters of plaque stability: plaque Tcell infiltration, cell death, collagen composition, and macrophage and vascular smooth muscle cell content were unchanged. These results show that CD8α + DC loss in hyperlipidemic mice profoundly reduces cross-priming ability, nevertheless it does not influence lesion development. Taken together, we clearly demonstrate that CD8α + DC-mediated cross-presentation does not significantly contribute to atherosclerotic plaque formation and stability.

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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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            Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells

            In recent years, human dendritic cells (DCs) could be subdivided into CD304+ plasmacytoid DCs (pDCs) and conventional DCs (cDCs), the latter encompassing the CD1c+, CD16+, and CD141+ DC subsets. To date, the low frequency of these DCs in human blood has essentially prevented functional studies defining their specific contribution to antigen presentation. We have established a protocol for an effective isolation of pDC and cDC subsets to high purity. Using this approach, we show that CD141+ DCs are the only cells in human blood that express the chemokine receptor XCR1 and respond to the specific ligand XCL1 by Ca2+ mobilization and potent chemotaxis. More importantly, we demonstrate that CD141+ DCs excel in cross-presentation of soluble or cell-associated antigen to CD8+ T cells when directly compared with CD1c+ DCs, CD16+ DCs, and pDCs from the same donors. Both in their functional XCR1 expression and their effective processing and presentation of exogenous antigen in the context of major histocompatibility complex class I, human CD141+ DCs correspond to mouse CD8+ DCs, a subset known for superior antigen cross-presentation in vivo. These data define CD141+ DCs as professional antigen cross-presenting DCs in the human.
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              Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8α+ dendritic cells

              In mouse, a subset of dendritic cells (DCs) known as CD8α+ DCs has emerged as an important player in the regulation of T cell responses and a promising target in vaccination strategies. However, translation into clinical protocols has been hampered by the failure to identify CD8α+ DCs in humans. Here, we characterize a population of human DCs that expresses DNGR-1 (CLEC9A) and high levels of BDCA3 and resembles mouse CD8α+ DCs in phenotype and function. We describe the presence of such cells in the spleens of humans and humanized mice and report on a protocol to generate them in vitro. Like mouse CD8α+ DCs, human DNGR-1+ BDCA3hi DCs express Necl2, CD207, BATF3, IRF8, and TLR3, but not CD11b, IRF4, TLR7, or (unlike CD8α+ DCs) TLR9. DNGR-1+ BDCA3hi DCs respond to poly I:C and agonists of TLR8, but not of TLR7, and produce interleukin (IL)-12 when given innate and T cell–derived signals. Notably, DNGR-1+ BDCA3+ DCs from in vitro cultures efficiently internalize material from dead cells and can cross-present exogenous antigens to CD8+ T cells upon treatment with poly I:C. The characterization of human DNGR-1+ BDCA3hi DCs and the ability to grow them in vitro opens the door for exploiting this subset in immunotherapy.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                21 October 2015
                2015
                : 5
                : 15414
                Affiliations
                [1 ]Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht , The Netherlands
                [2 ]Division of Immunobiology, Cincinnati Children’s Hospital Research Foundation, and the University of Cincinnati College of Medicine , Cincinnati, OH, United States of America
                [3 ]Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht , The Netherlands
                [4 ]Experimental Vascular Biology, Dept. of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam , Amsterdam, The Netherlands
                [5 ]Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University (LMU) , Munich, Germany
                [6 ]Institute for Biomedical Engineering, Dept. of Cell Biology, RWTH Aachen University Medical School , Aachen, Germany
                [7 ]Medical Immunology, Universitatsklinikum Erlangen , Erlangen, Germany
                Author notes
                Article
                srep15414
                10.1038/srep15414
                4614009
                26486587
                e625a731-78aa-4f7e-a6fe-5f0d0f0c469e
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 15 January 2015
                : 02 September 2015
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