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RBP-J Signaling − Cells Through Notch Novel IRF8-Controlled

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RBP-J Signaling − Cells Through Notch Novel IRF8-Controlled Sca-1+Lin−CD117− Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch −RBP-J Signaling This information is current as of September 25, 2021. Xingxia Liu, Shaoda Ren, Chaozhuo Ge, Kai Cheng, Martin Zenke, Armand Keating and Robert C. H. Zhao J Immunol 2015; 194:4298-4308; Prepublished online 30 March 2015; doi: 10.4049/jimmunol.1402641 Downloaded from http://www.jimmunol.org/content/194/9/4298 Supplementary http://www.jimmunol.org/content/suppl/2015/03/28/jimmunol.140264 http://www.jimmunol.org/ Material 1.DCSupplemental References This article cites 59 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/194/9/4298.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Sca-1+Lin2CD1172 Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch–RBP-J Signaling Xingxia Liu,*,1 Shaoda Ren,*,1 Chaozhuo Ge,* Kai Cheng,* Martin Zenke,† Armand Keating,‡,x and Robert C. H. Zhao* Mesenchymal stem/stromal cells (MSCs) can influence the destiny of hematopoietic stem/progenitor cells (HSCs) and exert broadly immunomodulatory effects on immune cells. However, how MSCs regulate the differentiation of regulatory dendritic cells (regDCs) from HSCs remains incompletely understood. In this study, we show that mouse bone marrow–derived Sca-1+Lin2CD1172 MSCs can drive HSCs to differentiate into a novel IFN regulatory factor (IRF)8–controlled regDC population (Sca+ BM-MSC–driven DC [sBM-DCs]) when cocultured without exogenous cytokines. The Notch pathway plays a critical role in the generation of the Downloaded from sBM-DCs by controlling IRF8 expression in an RBP-J–dependent way. We observed a high level of H3K27me3 methylation and a low level of H3K4me3 methylation at the Irf8 promoter during sBM-DC induction. Importantly, infusion of sBM-DCs could alleviate colitis in mice with inflammatory bowel disease by inhibiting lymphocyte proliferation and increasing the numbers of CD4+CD25+ regulatory T cells. Thus, these data infer a possible mechanism for the development of regDCs and further support the role of MSCs in treating immune disorders. The Journal of Immunology, 2015, 194: 4298–4308. http://www.jimmunol.org/ s an important component of the hematopoietic stem/ attractive because of their unique immunological characteristics, such progenitor cell (HSC) microenvironment, mesenchymal as low immunogenicity and immunoregulatory properties (3, 4). The A stromal/stem cells (MSCs) are capable of self-renewal and results from various studies have shown that MSCs are not able to multilineage differentiation (1, 2). However, MSCs are particularly stimulate T cell proliferation but can suppress T cell proliferation, and they also exert an inhibitory effect on the proliferation of B cells (5, 6). Additionally, MSCs might also act on dendritic cells (DCs) to *Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences, regulate immune responses (7); however, relatively little is known Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union about their effects on DC development and function. Medical College, Peking Union Medical College Hospital, Chinese Academy of by guest on September 25, 2021 Medical Sciences, Beijing 100005, People’s Republic of China; †Department of Cell DCs not only play a role in the initiation of immunity but also are Biology, Institute for Biomedical Engineering, Rhenish-Westphalian Technical indispensable for the preservation of tolerance. They work as pro- University, Aachen University Medical School, 52074 Aachen, Germany; ‡Cell Therapy x fessional APCs in promoting Ag-specific immune responses and are Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada; and Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario likewise implicated in tuning the balance between immunity and M5G 2M9, Canada tolerance induction (8, 9). DCs arise from HSCs and were initially 1X.L. and S.R. contributed equally to this work. identified by their potent activation of naive T cells (10). DCs can be Received for publication October 21, 2014. Accepted for publication February 27, divided into distinct subsets by anatomical location, and different 2015. subsets of classical DCs express a diversity of phenotype and function This work was supported by the National Key Scientific Program of China Grant and favor alternative modules of immunity (11–13). Recent findings 2011CB964901, Program for International Science and Technology Cooperation suggest that DC heterogeneity is developmentally determined, and it Projects of China Grant 2013DFG30680, National Natural Science Foundation of China Grants 81370879 and 81370466, National Science and Technology hasbeendifficulttoidentifytherelationships between these various Major Project of the Ministry of Science and Technology of China Grant cells based only on cell surface markers and functional responses. 2014ZX09101042, and by Key Program for Beijing Municipal Natural Science Foundation Grant 7141006. Consequently, understanding the molecular basis of DC development and diversification is important to better appreciate immune regula- Address correspondence and reprint requests to Prof. Robert C.H. Zhao, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic tion. Currently, the basis for DC development into the recognized Medicine, Peking Union Medical College, Peking Union Medical College Hospital, subsets/lineages is only partially understood, based on the require- Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences, 5 Dongdansantiao, Beijing 100005, People’s Republic of China. E-mail address: ments for several transcription factors, including PU.1, IFN regula- [email protected] tory factor (IRF)8, E2-2, IRF4, Batf3, Ikaros, GFi1, and ID2 (14-16). The online version of this article contains supplemental material. These transcription factors combine to form a transcriptional network Abbreviations used in this article: BM, bone marrow; BM-HSC, BM-derived hema- that gives rise to the phenotypically and functionally distinct subsets topoietic stem/progenitor cell; BM-MSC, BM-derived MSC; ChIP, chromatin immu- under steady-state conditions. It is now becoming evident that DC noprecipitation; DAPT, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine development is guided by lineage-restricted transcription factors such t-butyl ester; DC, dendritic cell; H3K4me3, trimethylation at lysine 4 of histone H3; H3K27me3, trimethylation at lysine 27 of histone H3; HSC, hematopoietic as IRF8, E2-2, and Batf3 (17-19). However, little is known regarding stem/progenitor cell; IBD, inflammatory bowel disease; imDC, immature DC; IRF, how cytokines and lineage-restricted transcription factors operate at IFN regulatory factor; maDC, mature DC; MSC, mesenchymal stem/stromal cell; PRC, polycomb repressive complex; qRT-PCR, quantitative RT-PCR; regDC, regu- a molecular level to direct DC diversification and development. latory DC; sBM-DC, Sca+ BM-MSC–driven DC; siRNA, small interfering RNA; The Notch family provides an evolutionarily conserved signaling TCF, T cell–specific factor; TNBS, 2,4,6-trinitrobenzene sulfonic acid; TRAF, network that plays a key role in the development of a variety of TNFR-associated factor. immune cells. To date, four Notch receptor family members and Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 five Notch ligands have been identified in mammalian cells (20, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402641 The Journal of Immunology 4299 21). Notch receptors are activated following binding of appro- acetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT; the cells in the priate ligands, which results in the nuclear translocation of the sBM-DCs plus DAPT group were treated with 20 mM DAPT that was Notch intracellular domain. The Notch intracellular domain dissolved in DMSO). DMSO or 20 mM DAPT (a Notch inhibitor, Tocris Bioscience) was added every 2 d; after coculture for 7 d, the remaining interacts with a number of cytoplasmic and nuclear proteins, loosely adherent cell clusters were collected for the following experiment. permitting signal transduction through several pathways that in- clude activation of the CBF-1/RBP-J transcription factor, which Flow cytometric analysis works as a negative regulator of lineage-specific gene expression Flow cytometric analysis was performed as previously described (39). The (22, 23). Several studies suggest possible involvement of Notch fluorescent Abs used in
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