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Vivo Blood and Tonsillar Dendritic Cells in Functionally Associated Gene Family Clustering Identifies Functionally Associated Subsets of Human In Vivo Blood and Tonsillar Dendritic Cells This information is current as Malin Lindstedt, Kristina Lundberg and Carl A. K. of September 26, 2021. Borrebaeck J Immunol 2005; 175:4839-4846; ; doi: 10.4049/jimmunol.175.8.4839 http://www.jimmunol.org/content/175/8/4839 Downloaded from References This article cites 28 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/175/8/4839.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 by guest on September 26, 2021 *average 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Gene Family Clustering Identifies Functionally Associated Subsets of Human In Vivo Blood and Tonsillar Dendritic Cells1 Malin Lindstedt,2* Kristina Lundberg,2* and Carl A. K. Borrebaeck3* Human dendritic cells (DCs) are a distinct but heterogeneous lineage of APCs operating as the link between innate and adaptive immune responses, with the function to either maintain tolerance or trigger immunity. The DC lineage consists of several sub- populations with unique phenotypes; however, their functional characteristics and transcriptional similarities remain largely unknown. To further characterize the phenotypes and transcriptomes of the subsets, we purified myeloid CD16؉, blood DC Ag .1؉ (BDCA1؉), and BDCA3؉ DC populations, as well as plasmacytoid CD123؉ DCs, from tonsillar tissue and peripheral blood Transcriptional profiling and hierarchical clustering visualized that BDCA1؉ DCs clustered with BDCA3؉ DCs, whereas CD16؉ Downloaded from DCs and CD123؉ DCs clustered as distinct populations in blood. Differential expression levels of chemokines, ILs, and pattern recognition receptors were demonstrated, which emphasize innate DC subset specialization. Even though highly BDCA1؉ and BDCA3؉ DC-specific gene expression was identified in blood, the BDCA1؉ DCs and BDCA3؉ DCs from tonsils displayed similar transcriptional activity, most likely due to the pathogenic or inflammatory maturational signals present in tonsillar tissues. Of note, plasmacytoid DCs displayed less plasticity in their transcriptional activity compared with myeloid DCs. The data demon- strated a functionally distinct association of each of the seven subsets based on their signatures, involving regulatory genes in http://www.jimmunol.org/ adaptive and innate immunity. The Journal of Immunology, 2005, 175: 4839–4846. endritic cells (DCs)4 constitute a distinct lineage of leu- ertheless, plasmacytoid CD123ϩ DCs and myeloid CD11cϩ DC pop- kocytes with exclusive features, such as initiation of T ulations have been defined in human thymus (4, 5), spleen (6), and D cell responses (1). Serving as the gatekeeper between the tonsils (7). The majority of human ex vivo DC studies have been innate and adaptive immune system, DCs are involved in the con- performed on DCs isolated from peripheral blood, which is a rela- trol of both tolerance and immunity. DCs have an outstanding tively consistent source of DCs. Based on lineage-specific marker capacity to present antigenic peptides in the context of MHC and negativity (LinϪ) and HLA-DRϩ, these DC populations have been selectively respond to environmental factors and pathogens fractionated primarily by using Abs against CD11c and CD123. Abs by guest on September 26, 2021 through the repertoire of pattern recognition receptors (PPRs). De- to the DC-specific markers blood DC Ag 1–4 (BDCA1 to -4) have spite many common features within the lineage, DCs comprise a enabled further characterization of different DC subpopulations (8). heterogeneous population of cells that originate from both lym- Thus far, five DC subsets, expressing unique phenotypes, have re- phoid and myeloid progenitors (2). Recent evidence also shows cently been identified in human blood based on their expression of that plasmacytoid DCs can originate from both lymphoid and my- CD123, CD1c/b, BDCA3, CD34, and CD16 (9). eloid pathways (3); however, the contribution of the respective pre- Even though several different DC subsets have been identified in cursors to the different DC subsets remains unclear. Multifaceted phe- blood, more information about their relationship, functional proper- notypes and specialized functions of the different DC subpopulations, ties, and tissue distribution is necessary. In this study, we further char- as well as their wide distribution, are factors that complicate the area acterized the CD1cϩ (BDCA1ϩ) DCs, BDCA3ϩ DCs, CD16ϩ DCs, of DC characterization. Their migratory behavior and membrane re- and CD123ϩ DCs isolated from peripheral blood, as well as identified organization during maturation further adds to the complexity. and phenotypically characterized BDCA1ϩ DCs, BDCA3ϩ DCs, and In contrast to the numerous studies performed in mice, only limited CD123ϩ DCs in human tonsils. In addition, we performed a global data are presently available on human DCs. Limited knowledge of transcriptional analysis of these discrete peripheral blood and tonsillar functionally associated DC subtypes, in combination with low fre- tissue DC subsets. We identified large clusters of DC subtype-specific quencies of tissue DCs, have hampered their characterization. Nev- gene expression and further analyzed their transcriptional relationship. Our data suggest that the defined subtypes are unique DC populations, exhibiting different repertoires of chemokine receptors, TLRs, and Department of Immunotechnology, Lund University, Lund, Sweden C-type lectins, indicating different functional roles. In addition to DC Received for publication April 27, 2005. Accepted for publication July 5, 2005. subtype-specific gene expression, we also identified transcription sig- ϩ ϩ The costs of publication of this article were defrayed in part by the payment of page natures common to BDCA1 DCs and BDCA3 DCs. These clusters charges. This article must therefore be hereby marked advertisement in accordance of DC-specific markers offer new insights in the ontogeny and func- with 18 U.S.C. Section 1734 solely to indicate this fact. tional role of the different DCs subsets, and for identification of novel 1 This work was supported by a grant from Vetenskapsra˚det. DC-specific markers. 2 M.L. and K.L. contributed equally to this article. 3 Address correspondence and reprint requests to Prof. Carl A. K. Borrebaeck, De- Materials and Methods partment of Immunotechnology, Lund University, P.O. Box 7031, S-220 07 Lund, Isolation of DC populations from tonsils and peripheral blood Sweden. E-mail address: [email protected] 4 Abbreviations used in this paper: DC, dendritic cell; BDCA, blood DC Ag; PPR, Human tonsils were obtained from children undergoing tonsillectomy at pattern recognition receptor; CLECSF, C-type lectin superfamily member. Lund University Hospital (Lund, Sweden). Tonsils were minced in RPMI Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 4840 TRANSCRIPTIONAL ANALYSIS OF HUMAN BLOOD AND TONSILLAR DCs 1640 medium (Sigma-Aldrich) supplemented with 0.2% gentamicin (In- analyzer (Agilent Technologies), and denatured at 94°C before hybridiza- vitrogen Life Technologies), and the tissue was digested with 2 mg/ml tion. The samples were hybridized to the Human Genome U133 Plus 2.0 collagenase IV and 100 U/ml DNase I for 15 min in room temperature. Array at 45°C for 16 h by rotation (60 rpm) in an oven. The arrays were Released cells were filtered through 70-␮m nylon cell strainers (Falcon; then washed, stained with streptavidin-PE (Molecular Probes), washed BD Biosciences) and washed once in gentamicin-supplemented RPMI again, and scanned with a GeneArray Scanner (Affymetrix). 1640. PBMC were isolated from leukocyte-enriched buffy coats (Lund University Hospital) by Ficoll-Paque (Amersham Biosciences) density gra- Microarray data analysis dient centrifugation. T lymphocytes were depleted by rosetting with sheep erythrocytes treated with neuraminidase (Sigma-Aldrich). Further deple- The fluorescence intensity was analyzed, using the GeneChip Operating tion of B cells, T cells, and monocytes was performed by magnetic sepa- Software (GCOS) 1.1 (Affymetrix), and scaled to a target value of 100. ration, using anti-CD19-, anti-CD3-, and anti-CD14-coated beads (Dynal Further data analysis was performed with GeneSpring 7.1 software. For Biotech). Negatively selected cells enriched for DCs were incubated with clustering, the samples were normalized both per chip, to the 50th percen- FITC-conjugated mAbs against CD3 (BD Biosciences), CD14 and CD19 tile, and per gene, which makes the median value for each gene across the (DakoCytomation), allophycocyanin-conjugated anti-HLA-DR (BD Bio- samples equal to 1. A tree clustering was performed on the individual
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