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Midkine Inhibits Inducible Regulatory T Cell Differentiation by Suppressing the Development of Tolerogenic Dendritic Cells

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Midkine Inhibits Inducible Regulatory T Cell Differentiation by Suppressing the Development of Tolerogenic Dendritic Cells Midkine Inhibits Inducible Regulatory T Cell Differentiation by Suppressing the Development of Tolerogenic Dendritic Cells This information is current as Yoshifumi Sonobe, Hua Li, Shijie Jin, Satoshi Kishida, of September 23, 2021. Kenji Kadomatsu, Hideyuki Takeuchi, Tetsuya Mizuno and Akio Suzumura J Immunol 2012; 188:2602-2611; Prepublished online 8 February 2012; doi: 10.4049/jimmunol.1102346 Downloaded from http://www.jimmunol.org/content/188/6/2602 Supplementary http://www.jimmunol.org/content/suppl/2012/02/08/jimmunol.110234 Material 6.DC1 http://www.jimmunol.org/ References This article cites 48 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/188/6/2602.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Midkine Inhibits Inducible Regulatory T Cell Differentiation by Suppressing the Development of Tolerogenic Dendritic Cells Yoshifumi Sonobe,* Hua Li,* Shijie Jin,* Satoshi Kishida,† Kenji Kadomatsu,† Hideyuki Takeuchi,* Tetsuya Mizuno,* and Akio Suzumura* Midkine (MK), a heparin-binding growth factor, reportedly contributes to inflammatory diseases, including Crohn’s disease and rheumatoid arthritis. We previously showed that MK aggravates experimental autoimmune encephalomyelitis (EAE) by decreas- ing regulatory CD4+CD25+Foxp3+ T cells (Tregs), a population that regulates the development of autoimmune responses, although the precise mechanism remains uncertain. In this article, we show that MK produced in inflammatory conditions suppresses the development of tolerogenic dendritic cells (DCregs), which drive the development of inducible Treg. MK suppressed DCreg- Downloaded from mediated expansion of the CD4+CD25+Foxp3+ Treg population. DCregs expressed significantly higher levels of CD45RB and produced significantly less IL-12 compared with conventional dendritic cells. However, MK downregulated CD45RB expression and induced IL-12 production by reducing phosphorylated STAT3 levels via src homology region 2 domain-containing phosphatase-2 in DCreg. Inhibiting MK activity with anti-MK RNA aptamers, which bind to the targeted protein to suppress the function of the protein, increased the numbers of CD11clowCD45RB+ dendritic cells and Tregs in the draining lymph nodes and suppressed the severity of EAE, an animal model of multiple sclerosis. Our results also demonstrated that MK was produced http://www.jimmunol.org/ by inflammatory cells, in particular, CD4+ T cells under inflammatory conditions. Taken together, these results suggest that MK aggravates EAE by suppressing DCreg development, thereby impairing the Treg population. Thus, MK is a promising therapeutic target for various autoimmune diseases. The Journal of Immunology, 2012, 188: 2602–2611. egulatory T cells (Tregs), characterized by the expression the combination of activated T cells and Smad3 (5, 6). Although of Foxp3, are potent immunomodulators that suppress these in vitro cytokine-mediated iTreg differentiation models help R proliferation and the release of proinflammatory cyto- to elucidate mechanisms of immune regulation, they do not nec- kines from effector T cells (1). Modulating Treg differentiation is essarily reflect the precise in vivo processes. critical for controlling various autoimmune diseases, including Th cell differentiation requires Ag presentation by APCs, such by guest on September 23, 2021 multiple sclerosis (MS), type 1 diabetes, and inflammatory bowel as dendritic cells (DCs). Although these cells can promote adap- disease (2–4). Stimulation of naive CD4+ T cells with TGF-b tive immune responses, stimulating DCs with such suppressive causes inducible Treg (iTreg) differentiation, which is character- factors as TGF-b, IL-10, galectin-1, vasoactive intestinal peptide, ized by Foxp3 expression via the RUNX transcription factors or and 1,25-dihydroxyvitamin D3 induces self-tolerance in vitro and in vivo (7–11). Previous reports showed that DCs stimulated with TGF-b and IL-10 elicit CD4+CD25+Foxp3+ Treg differentiation *Department of Neuroimmunology, Research Institute of Environmental Medicine, + Nagoya University, Nagoya 464-8601, Japan; and †Department of Biochemistry, from naive CD4 T cells (8, 12, 13). These results suggest that Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan regulation of these Treg-inducing tolerogenic DCs (DCregs) may Received for publication August 16, 2011. Accepted for publication January 6, 2012. provide therapeutic approaches for autoimmune diseases. This work was supported in part by the YOKOYAMA Foundation for Clinical The heparin-binding growth factor midkine (MK) was originally Pharmacology; a Grant-in-Aid for Scientific Research (Young Scientists B) and the identified as a gene expressed in response to retinoic acid (14). MK Global Centers of Excellence Program “Integrated Functional Molecular Medicine for Neuronal and Neoplastic Disorders” from the Ministry of Education, Culture, is thought to play a role in a number of inflammatory diseases, Sports, Science and Technology of Japan; Health and Labor Science Research Grants including cisplatin-induced renal damage, Crohn’s disease (CD), for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare; and rheumatoid arthritis (RA) (15–18). Our previous study showed the Program for Promotion of Fundamental Studies in Health Sciences of the Na- tional Institute of Biomedical Innovation; and a grant from the New Energy and that inhibiting MK activity alleviated experimental autoimmune Industrial Technology Development Organization of Japan. encephalomyelitis (EAE), an animal model of MS, by expanding Address correspondence and reprint requests to Dr. Yoshifumi Sonobe, Department the Treg population (19). However, the precise mechanisms that of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya Univer- regulate Treg proliferation remain largely unknown. sity, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail address: sonobe@riem. nagoya-u.ac.jp In this article, we show that inhibiting MK activity expands the The online version of this article contains supplemental material. DCreg population, which causes iTreg differentiation from naive CD4+ T cells. MK suppressed the development of DCregs in vitro Abbreviations used in this article: CD, Crohn’s disease; DC, dendritic cell; DCcon, conventional dendritic cell; DCreg, regulatory T cell-inducing tolerogenic dendritic and in vivo, and it induced IL-12 production by these cells by cell; dLN, draining lymph node; EAE, experimental autoimmune encephalomyelitis; downregulating levels of phosphorylated STAT3 (pSTAT3) via src iTreg, inducible regulatory T cell; KO, knockout; MK, midkine; MOG, myelin oli- godendrocyte glycoprotein; MS, multiple sclerosis; PD-L1, programmed cell death homology region 2 domain-containing phosphatase (SHP)-2. The ligand 1; pSTAT, phosphorylated STAT; RA, rheumatoid arthritis; rm, recombinant overall result was reduced DCreg-mediated iTreg differentiation. murine; SHP, src homology region 2 domain-containing phosphatase; Treg, regula- Inhibiting MK using RNA aptamers significantly suppressed EAE. tory T cell; WT, wild-type. MK was produced by inflammatory cells, in particular CD4+ Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 T cells under inflammatory conditions. Taken together, these www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102346 The Journal of Immunology 2603 results suggest that MK produced by CD4+ T cells aggravates 500 ng/ml ionomycin. After staining with PerCP–anti-CD4 Abs, cells were EAE by suppressing DCreg development and subsequent iTreg fixed and permeabilized with Cytofix/Cytoperm reagent (BD Biosciences) differentiation. Thus, expanding the iTreg population by inhibiting and stained with FITC–anti-IFN-g (XMG1.2; BD Biosciences) and PE– anti-IL-17 (TC11-18H10; BD Biosciences) Abs. The samples were ex- MK activity and DCreg proliferation may provide a useful strat- amined with a Cytomics FC500 system (Beckman Coulter) and analyzed egy for treating autoimmune diseases, including MS. with CXP Software Ver. 2.0 (Beckman Coulter). Materials and Methods MLR Animals CD4+CD252 T cells were isolated from the spleens of BALB/c mice using a MACS system (Miltenyi Biotec). CD4+CD252 T cells (H2d) were b d Female C57BL/6 (H2 ) and BALB/c (H2 ) mice were obtained from Japan cocultured for 4 d with DCcons, MK-treated DCcons, DCregs, or MK- SLC. MK-knockout (KO) mice (C57BL/6) were generated as described treated DCregs from C57BL/6 mice (H2b) at 1:1 ratios in the presence previously (19). Mice were bred in the animal facility of the Research or absence of rIL-12p70, anti–IL-12p40 Abs (C17.8; BD Biosciences),
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