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      Characterization of resident and migratory dendritic cells in human lymph nodes

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          Abstract

          Human skin-draining lymph nodes contain functionally distinct subsets of resident and migratory dendritic cells.

          Abstract

          Dendritic cells (DCs) initiate adaptive immune responses in lymph nodes (LNs). In mice, LN DCs can be divided into resident and tissue-derived populations, the latter of which migrate from the peripheral tissues. In humans, different subsets of DCs have been identified in the blood, spleen, and skin, but less is known about populations of resident and migratory tissue-derived DCs in LNs. We have analyzed DCs in human LNs and identified two populations of resident DCs that are present in all LNs analyzed, as well as in the spleen and tonsil, and correspond to the two known blood DC subtypes. We also identify three main populations of skin-derived migratory DCs that are present only in skin-draining LNs and correspond to the DC subsets found in the skin. Resident DCs subsets induce both Th1 and Th2 cytokines in naive allogeneic T lymphocytes, whereas the corresponding blood subsets failed to induce efficient Th2 polarization. LN-resident DCs also cross-present antigen without in vitro activation, whereas blood DCs fail to do so. Among migratory DCs, one subset was poor at both CD4 + and CD8 + T cell activation, whereas the other subsets induced only Th2 polarization. We conclude that in humans, skin-draining LNs host both resident and migratory DC subsets with distinct functional abilities.

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          Most cited references23

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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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            CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions.

            The CC chemokine receptor CCR7 has been identified as a key regulator of homeostatic B and T cell trafficking to secondary lymphoid organs. Data presented here demonstrate that CCR7 is also an essential mediator for entry of both dermal and epidermal dendritic cells (DC) into the lymphatic vessels within the dermis while this receptor is dispensable for the mobilization of Langerhans cells from the epidermis to the dermis. Moreover, a distinct population of CD11c(+)MHCII(high) DC showing low expression of the costimulatory molecules CD40, CD80, and CD86 in wild-type animals was virtually absent in skin-draining lymph nodes of CCR7-deficient mice under steady-state conditions. We provide evidence that these cells represent a semimature population of DC that is capable of initiating T cell proliferation under conditions known to induce tolerance. Thus, our data identify CCR7 as a key regulator that governs trafficking of skin DC under both inflammatory and steady-state conditions.
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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
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                9 April 2012
                : 209
                : 4
                : 653-660
                Affiliations
                [1 ]Institut National de la Santé et de la Recherche Médicale Unité 932, 75005 Paris, France
                [2 ]Centre de Recherche , [3 ]Laboratoire d’Immunologie Clinique , and [4 ]Département de Biologie des Tumeurs, Institut Curie, 75005 Paris, France
                [5 ]CBT507 Institut Gustave Roussy–Curie (Institut National de la Santé et de la Recherche Médicale Centre d’Investigation Clinique), 75005 Paris, France
                [6 ]Le Centre de Recherche en Cancérologie de Lyon, Institut National de la Santé et de la Recherche Médicale Unité 1052, Centre National de la Recherche Scientifique 5286, Centre Léon Bérard, 69008 Lyon, France
                Author notes
                CORRESPONDENCE Sebastian Amigorena: sebastian.amigorena@ 123456curie.fr
                Article
                20111457
                10.1084/jem.20111457
                3328358
                22430490
                49fe80f5-e7b6-4333-90c8-54b78506313d
                © 2012 Segura et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 15 July 2011
                : 21 February 2012
                Categories
                Brief Definitive Report

                Medicine
                Medicine

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