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Regulation Pathway of Mesenchymal Stem Cell Immune Dendritic Cell Downloaded from http://www.jimmunol.org/ by guest on September 26, 2021 is online at: average * The Journal of Immunology , 13 of which you can access for free at: 2010; 185:5102-5110; Prepublished online 1 from submission to initial decision 4 weeks from acceptance to publication October 2010; doi: 10.4049/jimmunol.1001332 http://www.jimmunol.org/content/185/9/5102 Inhibition of Immune Synapse by Altered Dendritic Cell Actin Distribution: A New Pathway of Mesenchymal Stem Cell Immune Regulation Alessandra Aldinucci, Lisa Rizzetto, Laura Pieri, Daniele Nosi, Paolo Romagnoli, Tiziana Biagioli, Benedetta Mazzanti, Riccardo Saccardi, Luca Beltrame, Luca Massacesi, Duccio Cavalieri and Clara Ballerini J Immunol cites 38 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2010/10/01/jimmunol.100133 2.DC1 This article http://www.jimmunol.org/content/185/9/5102.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 26, 2021. The Journal of Immunology Inhibition of Immune Synapse by Altered Dendritic Cell Actin Distribution: A New Pathway of Mesenchymal Stem Cell Immune Regulation Alessandra Aldinucci,* Lisa Rizzetto,† Laura Pieri,‡ Daniele Nosi,‡ Paolo Romagnoli,‡ Tiziana Biagioli,* Benedetta Mazzanti,x Riccardo Saccardi,x Luca Beltrame,† Luca Massacesi,* Duccio Cavalieri,† and Clara Ballerini* Immune synapse formation between dendritic cells (DCs) and T cells is one of the key events in immune reaction. In immunogenic synapses, the presence of fully mature DCs is mandatory; consequently, the modulation of DC maturation may promote tolerance and represents a valuable therapeutic approach in autoimmune diseases. In the field of cell therapy, bone marrow mesenchymal stem cells (MSCs) have been extensively studied for their immunoregulatory properties, such as inhibiting DC immunogenicity Downloaded from during in vitro differentiation and ameliorating in vivo models of autoimmune diseases (e.g., experimental allergic encephalomyelitis). MSCs seem to play different roles with regard to DCs, depending on cell concentration, mechanism of stimulation, and accompanying immune cells. The aim of this work was to elucidate the immunogenic effects of MSC/DC interactions during DC activation (LPS stimulation or Ag loading). Human monocyte-derived DCs, bone marrow-derived MSCs, and circulating lymphocytes obtained from healthy donors, as well as the laboratory-generated influenza virus hemagglutinin-derived peptide, aa 306–318 peptide-specific T cell line were used for this study. We demonstrate that MSCs mediate inhibition of DC function only upon cell–cell contact. Despite no http://www.jimmunol.org/ modification observed in cell phenotype or cytokine production, MSC-treated DCs were unable to form active immune synapses; they retained endocytic activity and podosome-like structures, typical of immature DCs. The transcriptional program induced by MSC– DC direct interaction supports at the molecular pathway level the phenotypical features observed, indicating the genes involved into contact-induced rearrangement of DC cytoskeleton. The Journal of Immunology, 2010, 185: 5102–5110. one marrow mesenchymal stem cells (MSCs) are multi- cross-talk between MSCs and T cells may be responsible for T cell potent cells able to differentiate in vitro and in vivo into immunosuppression, and LPS stimulation may inhibit this sup- by guest on September 26, 2021 B tissues of mesenchymal and nonmesenchymal origin. pression by downregulating Jagged1 expression via TLR4 (4). MSCs have been extensively studied for their immunoregulatory However, even if MSC stimulation by LPS is followed by upreg- properties, and there is wide agreement that they inhibit in vitro ulation of TLR4 expression, it does not affect the ability of MSCs to T cell proliferation and dendritic cell (DC) immunogenicity and induce the differentiation of nonimmunogenic DCs (5). Conflicting can ameliorate in vivo autoimmune diseases, such as experimental results were reported for MSC/B cell interaction. Corcione et al. (6) allergic encephalomyelitis (1, 2). MSCs have been approved as showed MSC-mediated inhibition of the proliferation and differ- treatment for severe graft-versus-host disease (3). A Notch-Jagged1 entiation of human peripheral B cells into Ig-secreting cells; in contrast, a more recent study concluded that B cells can efficiently respond to the TLR9 agonist CpG 2006 in the absence of BCR triggering when cocultured with MSCs and that MSCs stimulate the *Department of Neurological Sciences, †Department of Pharmacology, and proliferation and differentiation of B into Ig-secreting cells isolated ‡Department of Anatomy, Histology and Forensic Medicine, University of Flor- ence; and xDepartment of Hematology, Careggi Hospital, Florence, Italy from patients affected by systemic lupus erythematosus (7). The extent to which the effects of MSCs on immune-system cells are Received for publication April 23, 2010. Accepted for publication August 20, 2010. mediated by soluble factors and/or cell–cell contact has yet to be This work was supported in part by the Italian Ministry of Education, Universities and Research (Grant 2007LTAJMA_003 to P.R.) and by the European Community fully understood. Different properties of MSCs may depend on the projects sixth frame program (FP6) Network of Excellence DC-THERA, EU LSHB- mechanism of stimulation, cell concentration, and type of coex- CT-2004-512074 and FP7 Integrative Project SYBARIS (Grant 242220), and MIUR isting immune cells. Progetti di Ricerca di Interesse Nazionale 519MIUR060 (to D.C.). Focusing our research on MSC/DC interactions during DC Address correspondence and reprint requests to Dr. Clara Ballerini, Department of Neurological Sciences, University of Florence, Viale Pieraccini, 6, 50139 Florence, activation, we show that upon direct physical interaction with Italy. E-mail address: clara.ballerini@unifi.it MSCs, DCs become unable to form active immune synapses with The online version of this article contains supplemental material. lymphocytes, despite their expression of a mature phenotype and Abbreviations used in this paper: BG, background; ctr, control; DC, dendritic cell; normal IL-12/IL-10–production profile. In contrast, MSC-treated DEG, differentially expressed gene; FAK, focal adhesion kinase; FluHA 316–318, DCs retain endocytic activity and podosome-like structures, typ- influenza virus hemagglutinin-derived peptide, aa 306–318; KEGG, Kyoto Encyclo- pedia of Genes and Genomes; MSC, mesenchymal stem cell; MYL9, myosin regu- ical of “immature” DCs. We also show that the behavior of MSC- latory L chain 9; MYLK, myosin L chain kinase; NIH, National Institutes of Health; treated DCs is accompanied by rearrangement of the cytoskeleton sBEF, signed binary enrichment factor; STRING, Search Tool for the Retrieval of and reprogramming of mRNA expression, as well as that cell–cell Interacting Genes/Proteins; tw, Transwell. contact, assessed by electron microscopy, is mandatory for MSC- Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 mediated inhibition of DC immunogenicity. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001332 The Journal of Immunology 5103 Materials and Methods (1:200; Sigma-Aldrich); or monoclonal mouse anti-human Rac1 (2 mg/ml; Cells USBiological), followed by Alexa Fluor 488-conjugated rabbit anti-mouse IgG (1:200; Molecular Probes). DCs were generated from human monocytes of healthy donors, as pre- Confocal images were acquired using a Leica TCS SP5 microscope viously described (8). Briefly, anti-CD14+ monocytes were positively (Leica Microsystems, Mannheim, Germany) equipped with a He/Ne/Ar sorted by magnetic microbeads (Miltenyi Biotec, Bologna, Italy). Mono- laser source, using a Leica Plan Apo 363/1.40 NA oil-immersion objec- cytes were cultured for 6 d in medium supplemented with GM-CSF (1000 tive. A series of optical sections (1024 3 1024 pixels each; pixel size, 200 3 U/ml) and IL-4 (1000 U/ml; both from Labogen, Milano, Italy). Immature 200 nm) was taken at intervals of 0.35 mm. Confocal images were DCs were activated by 24 h of incubation with LPS (1 mg/ml; Sigma- deconvolved using ImageJ 3D deconvolution software (National Insti- Aldrich, St. Louis, MO) or 3 h of Ag loading (10 mg/ml, influenza virus tutes of Health [NIH], Bethesda, MD). Densitometric analysis was per- hemagglutinin-derived peptide, aa 306–318 [FluHA 306–318], kindly formed with ImageJ software (NIH), measuring the average fluore- provided by Anna Maria Papini, PeptLab, Department of Organic Chem- scence intensity on regions of interest in single focal-plane images. istry, University of Florence). CD4+ T cells were negatively selected from PBMCs using the T cell isolation kit II from Miltenyi Biotec. The FluHA T cell-proliferation tests 306–318–specific T cell
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