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      Human in vivo-generated monocyte-derived dendritic cells and macrophages cross-present antigens through a vacuolar pathway

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          Abstract

          Presentation of exogenous antigens on MHC-I molecules, termed cross-presentation, is essential for cytotoxic CD8 + T cell responses. In mice, dendritic cells (DCs) that arise from monocytes (mo-DCs) during inflammation have a key function in these responses by cross-presenting antigens locally in peripheral tissues. Whether human naturally-occurring mo-DCs can cross-present is unknown. Here, we use human mo-DCs and macrophages directly purified from ascites to address this question. Single-cell RNA-seq data show that ascites CD1c + DCs contain exclusively monocyte-derived cells. Both ascites mo-DCs and monocyte-derived macrophages cross-present efficiently, but are inefficient for transferring exogenous proteins into their cytosol. Inhibition of cysteine proteases, but not of proteasome, abolishes cross-presentation in these cells. We conclude that human monocyte-derived cells cross-present exclusively using a vacuolar pathway. Finally, only ascites mo-DCs provide co-stimulatory signals to induce effector cytotoxic CD8 + T cells. Our findings thus provide important insights on how to harness cross-presentation for therapeutic purposes.

          Abstract

          Cross-presentation, or the presentation of exogenous antigens on MHC-I, is thought to be restricted to dendritic cells (DCs). Here the authors show that human DCs and macrophages developed in vivo from monocytes can both perform cross-presentation using a non-conventional pathway, but only DCs are capable of inducing cytotoxic CD8 + T cells.

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          Most cited references 46

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          Human inflammatory dendritic cells induce Th17 cell differentiation.

          Dendritic cells (DCs) are critical regulators of immune responses. Under noninflammatory conditions, several human DC subsets have been identified. Little is known, however, about the human DC compartment under inflammatory conditions. Here, we characterize a DC population found in human inflammatory fluids that displayed a phenotype distinct from macrophages from the same fluids and from steady-state lymphoid organ and blood DCs. Transcriptome analysis showed that they correspond to a distinct DC subset and share gene signatures with in vitro monocyte-derived DCs. Moreover, human inflammatory DCs, but not inflammatory macrophages, stimulated autologous memory CD4(+) T cells to produce interleukin-17 and induce T helper 17 (Th17) cell differentiation from naive CD4(+) T cells through the selective secretion of Th17 cell-polarizing cytokines. We conclude that inflammatory DCs represent a distinct human DC subset and propose that they are derived from monocytes and are involved in the induction and maintenance of Th17 cell responses. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells.

            Little is known about the functional differences between the human skin myeloid dendritic cell (DC) subsets, epidermal CD207(+) Langerhans cells (LCs) and dermal CD14(+) DCs. We showed that CD14(+) DCs primed CD4(+) T cells into cells that induce naive B cells to switch isotype and become plasma cells. In contrast, LCs preferentially induced the differentiation of CD4(+) T cells secreting T helper 2 (Th2) cell cytokines and were efficient at priming and crosspriming naive CD8(+) T cells. A third DC population, CD14(-)CD207(-)CD1a(+) DC, which resides in the dermis, could activate CD8(+) T cells better than CD14(+) DCs but less efficiently than LCs. Thus, the human skin displays three DC subsets, two of which, i.e., CD14(+) DCs and LCs, display functional specializations, the preferential activation of humoral and cellular immunity, respectively.
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              CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens.

              The generation of tumor-directed cytotoxic T lymphocytes is considered crucial for the induction of antitumor immunity. To activate these CD8(+) T cells, antigen-presenting cells (APCs) must initially acquire tumor cell-associated antigens. The major source of tumor antigens is dead tumor cells, but little is known about how APCs in draining lymph nodes acquire and crosspresent these antigens. Here we show that CD169(+) macrophages phagocytose dead tumor cells transported via lymphatic flow and subsequently crosspresent tumor antigens to CD8(+) T cells. Subcutaneous immunization with irradiated tumor cells protects mice from syngenic tumor. However, tumor antigen-specific CD8(+) T cell activation and subsequent antitumor immunity are severely impaired in mice depleted with CD169(+) macrophages. Neither migratory dendritic cells (DCs) nor lymph node-resident conventional DCs are essential for the crosspresentation of tumor antigens. Thus, we have identified CD169(+) macrophages as lymph node-resident APCs dominating early activation of tumor antigen-specific CD8(+) T cells. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                elodie.segura@curie.fr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                2 July 2018
                2 July 2018
                2018
                : 9
                Affiliations
                [1 ]Institut Curie, PSL Research University, INSERM, U932, 26 rue d’Ulm, 75005 Paris, France
                [2 ]GRID grid.417924.d, Sanofi, Breakthrough Laboratory, ; 1 Impasse des Ateliers, 94400 Vitry-sur-Seine, France
                [3 ]ISNI 0000 0004 0639 6384, GRID grid.418596.7, Institut Curie, PSL Research University, NGS Platform, ; 26 rue d’Ulm, 75005 Paris, France
                Article
                4985
                10.1038/s41467-018-04985-0
                6028641
                29967419
                © 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/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001665, Agence Nationale de la Recherche (French National Research Agency);
                Award ID: ANR-CHIN-0002
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000781, EC | European Research Council (ERC);
                Award ID: 2013-AdG 340046 DCBIOX
                Award Recipient :
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