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Dermal Fibroblasts Induce Maturation of Dendritic Cells Dermal Fibroblasts Induce Maturation of Dendritic Cells Anja Saalbach, Claudia Klein, Jonathan Sleeman, Ulrich Sack, Friederike Kauer, Carl Gebhardt, Marco Averbeck, Ulf This information is current as Anderegg and Jan C. Simon of October 2, 2021. J Immunol 2007; 178:4966-4974; ; doi: 10.4049/jimmunol.178.8.4966 http://www.jimmunol.org/content/178/8/4966 Downloaded from References This article cites 40 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/178/8/4966.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dermal Fibroblasts Induce Maturation of Dendritic Cells1 Anja Saalbach,2* Claudia Klein,* Jonathan Sleeman,‡ Ulrich Sack,† Friederike Kauer,* Carl Gebhardt,* Marco Averbeck,* Ulf Anderegg,* and Jan C. Simon* To trigger an effective T cell-mediated immune response in the skin, cutaneous dendritic cells (DC) migrate into locally draining lymph nodes, where they present Ag to naive T cells. Little is known about the interaction of DC with the various cellular microenvironments they encounter during their migration from the skin to lymphoid tissues. In this study, we show that human ␤ DC generated from peripheral blood monocytes specifically interact with human dermal fibroblasts via the interaction of 2 integrins on DC with Thy-1 (CD90) and ICAM-1 on fibroblasts. This induced the phenotypic maturation of DC reflected by expression of CD83, CD86, CD80, and HLA-DR in a TNF-␣- and ICAM-1-dependent manner. Moreover, fibroblast-matured DC potently induced T cell activation reflected by CD25 expression and enhanced T cell proliferation. Together these data demon- strate that dermal fibroblasts that DC can encounter during their trafficking from skin to lymph node can act as potent regulators of DC differentiation and function, and thus may actively participate in the regulation and outcome of DC-driven cutaneous Downloaded from immune responses. The Journal of Immunology, 2007, 178: 4966–4974. endritic cells (DC)3 are specialized APCs that are pivotal types. There is accumulating evidence that the stromal microen- in initiating immune responses. As sentinel cells of pe- vironment plays an important role in the regulation of DC func- D ripheral tissues, DC reside in and traffic through non- tions and in the priming of DC. Dudda et al. (5, 6) demonstrated lymphoid peripheral tissues, continuously surveying the environ- that intracutaneously injected bone marrow-derived DC can induce http://www.jimmunol.org/ ment for invading microorganisms. Under steady-state conditions skin-homing CD8ϩ T cells that express the cutaneous vascular and in the absence of microbial stimulation or inflammation, ap- entry code (cutaneous leukocyte Agϩ). T cells induced after i.p. parently immature DC capture Ags from apoptotic cells, transport injection of the same bone marrow-derived DC, however, them to secondary lymphoid organs, and are involved in the main- ␣ ␤ expressed the intestinal entry code (integrin 4 7). These experi- tenance of tolerance (1, 2). In contrast, the contact of DC with ments prove that DC possess enough plasticity to acquire tissue- danger signals such as microbial agents or inflammatory mediators specific signals from their local microenvironment and subse- induces the maturation of DC, resulting in an increase in their quently to instruct T cells for tissue-selective homing. Stromal expression of MHC molecules, costimulatory molecules, and cells such as fibroblasts, endothelial cells, and macrophages dis- cytokines, and an enhancement of their migratory capacity (3). play different functional properties, including migratory capacity, by guest on October 2, 2021 DC subsequently migrate from the periphery to the T cell zone contractility, and extracellular matrix production and degradation of secondary lymphoid organs (4). Thus, activated DC are spe- that are dependent on the anatomical site or disease status (7). cialized cells that obtain information from the periphery and Thus, it seems plausible that DC may receive instructions from transfer it to lymphoid organs, where they display Ags to naive stromal cells and/or their secreted products. Furthermore, recent Ag-specific T cells and thereby initiate primary T cell immune evidence suggests that the stromal microenvironment directly responses. affects the behavior and differentiation of DC. For example, When traveling from peripheral to lymphoid tissues, DC interact endothelial cells are able to influence the differentiation and with the stromal microenvironment that is composed of the extra- activation of DC (8, 9). cellular matrix, soluble mediators, and a variety of different cell Fibroblasts are an extremely heterogeneous multifunctional cell population, and their role in wound healing, developmental processes, and tumor development is well established (10). *Department of Dermatology, Venerology, and Allergology, Medical Faculty of Leipzig University, Leipzig, Germany; †Institute of Clinical Immunology and Trans- Nevertheless, immunologists have regarded fibroblast activa- fusion Medicine, Medical Faculty of Leipzig University, Leipzig, Germany; and ‡Re- tion as relatively unimportant in regulating immune responses search Centre Karlsruhe, Institute of Toxicology and Genetics, Karlsruhe, Germany and have focused on cellular interactions between lymphocytes, Received for publication October 4, 2006. Accepted for publication January 22, 2007. macrophages, and dendritic cells, all of which generate Ag- The costs of publication of this article were defrayed in part by the payment of page specific responses (11). However, fibroblasts are capable of pro- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ducing various paracrine immune modulators, such as peptide growth factors, cytokines, chemokines, and inflammatory me- 1 This work was supported by the German Research Foundation (Deutsche For- schungsgemeinschaft SA863/1-3, Te284/2-2) and the Interdisciplinary Center of Clin- diators (12). Additionally, they express cell surface adhesion ical Research Leipzig at the Faculty of Medicine of the Universita¨t Leipzig (Project molecules and costimulatory molecules such as CD40 (13). Fur- Z14(INT05)). thermore, there is abundant evidence that fibroblasts taken from 2 Address correspondence and reprint requests to Dr. Anja Saalbach, Department of Dermatology, Venerology, and Allergology, Medical Faculty of Leipzig University, diseased tissues display a fundamentally different phenotype Johannisallee 30, 04103 Leipzig, Germany. E-mail address: Anja.Saalbach@medizin. compared with fibroblasts taken from normal tissues of the uni-leipzig.de same anatomical site (14, 15). Fibroblasts might therefore not 3 Abbreviations used in this paper: DC, dendritic cell; CFDA, carboxyfluorescein only be purely structural elements, but potentially could also diacetate succinimidyl ester; CHO, Chinese hamster ovary. actively participate in the regulation of inflammation and im- Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 mune responses. www.jimmunol.org The Journal of Immunology 4967 In this study, we found human DC in close proximity to dermal incubated with 1 ␮g of anti-TNF-␣ Ab (R&D Systems) or an isotype fibroblasts in vivo. We also report that monocyte-derived DC have control Ab for 60 min at 4°C. After extensive washing with PBS/10% the capacity to adhere specifically to human dermal fibroblasts in Gelafusal, cells were incubated with a Cy2-labeled goat anti-mouse Ab (Dianova) for 60 min at 4°C. For the identification of the cell source of vitro. This interaction of immature DC with fibroblasts induced the TNF-␣, DC were identified by an anti-CD11c PE Ab. maturation of DC in a manner that was dependent on cell-cell contact as well as on soluble mediators. Fibroblast-induced DC Analysis of phagocytic ability maturation was accompanied by up-regulation of HLA, costimu- Immature DC, LPS-stimulated DC, or fibroblast-stimulated DC (5 ϫ 105) latory molecules and cytokines, and the acquisition of an allo- were incubated for 45 min at 37°C with 1 ϫ 107 FITC-conjugated Esch- stimulatory capacity to activate T cells. In summary, we demon- erichia coli (Invitrogen Life Technologies) in RPMI 1640 medium con- strate for the first time that fibroblasts actively participate in the taining 10% FCS. They were then washed twice with ice-cold PBS, resus- pended in ice-cold PBS, and immediately analyzed using flow cytometry. regulation of DC function. This results in the maturation of DC and Cells incubated at 4°C were used as negative controls. To quench the subsequent effective T cell activation,
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