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Paracrine-Induced Response State Antiviral-Activated Dendritic Cells: A

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Antiviral-Activated Dendritic Cells: A Paracrine-Induced Response State Antonio V. Bordería, Boris M. Hartmann, Ana Fernandez-Sesma, Thomas M. Moran and Stuart C. Sealfon This information is current as of September 24, 2021. J Immunol 2008; 181:6872-6881; ; doi: 10.4049/jimmunol.181.10.6872 http://www.jimmunol.org/content/181/10/6872 Downloaded from References This article cites 53 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/181/10/6872.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 September 24, 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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Antiviral-Activated Dendritic Cells: A Paracrine-Induced Response State1 Antonio V. Bordería,2* Boris M. Hartmann,2† Ana Fernandez-Sesma,* Thomas M. Moran,* and Stuart C. Sealfon3†‡ Infection of immature dendritic cells (DCs) by virus stimulates their maturation into APC. Infected DCs can also expose uninfected DCs to a panoply of cytokines/chemokines via paracrine signaling. Mathematical modeling suggests that a high rate of paracrine signaling is likely to occur among DCs located in three-dimensional space. Relatively little is known about how secreted factors modify the early response to virus infection. We used a transwell experimental system that allows passage of secreted factors, but not direct contact, between virus-infected DCs and uninfected DCs to investigate paracrine signaling responses. Paracrine signaling from infected DCs induced an antiviral-primed DC state distinct from that of mature virus-infected DCs that we refer to as antiviral-activated DCs (AVDCs). AVDCs had increased surface MHC class II and CD86 levels, but in contrast to virus-infected DCs, their MHC class I levels Downloaded from were unchanged. Imaging flow cytometry showed that AVDCs had an increased rate of phagocytosis compared with naive DCs. Experiments with IFN-␤ cytokine indicated that it may be responsible for CD86, but not MHC class II regulation in AVDCs. Both IFN-inducible and IFN-independent genes are up-regulated in AVDCs. Notably, AVDCs are relatively resistant to virus infection in comparison to naive DCs and achieve accelerated and augmented levels of costimulatory molecule expression with virus infection. AVDCs show a distinct antiviral-primed state of DC maturation mediated by DC paracrine signaling. Although further in vivo study is needed, the characteristics of the AVDC suggest that it is well suited to play a role in the early innate-adaptive transition of the immune http://www.jimmunol.org/ system. The Journal of Immunology, 2008, 181: 6872–6881. endritic cells (DCs)4 are recognized as a key bridge be- TLR-independent intracellular viral product detectors such as RIG-I tween the innate and adaptive immune responses (1). A (8) and/or MDA5 (9, 10). Virus recognition activates a signaling cas- D key event in the development of adaptive immunity cade involving different cellular factors (IFN regulatory factor 3, NF- upon exposure to infection is the maturation of DCs into APCs that ␬B, c-jun), causing the expression of type I IFNs and other inflam- instruct lymphocytes to generate responses to specific Ags. Acti- matory response genes including TNF-␣ and IL-6. The first type I IFN vated DCs efficiently stimulate both innate immune cells, includ- to be produced and secreted is IFN-␤ (11), which signals either in an by guest on September 24, 2021 ing NK cells (2) and NKT cells (3) as well as key components of autocrine or paracrine manner through the IFN receptor (IFNAR) and adaptive immunity including naive (4) and memory (5) B cells and activates the JAK-STAT pathway (12). This signaling cascade further T cells (1). Thus, DCs are important both for innate immunity as amplifies the initial response and creates an antiviral state in adjacent well as for various elements of adaptive immunity (6). cells that renders them resistant to infection. Our study focuses on DC activation by virus infection, using New- Maturation is a complex process, which includes changes in castle disease virus (NDV), a RNA paramyxovirus that has been dem- morphology, loss of endocytic/phagocytic receptors, up-regulation onstrated to be a good model for immune activation (7). DC matura- of costimulatory molecules, such as CD86, translocation of MHC tion is stimulated by detection of various pathogen-associated compartments to the surface, and secretion of cytokines and che- molecular patterns (1) that are characteristic of bacteria, fungi, proto- mokines (13) that attract, differentiate, and polarize other immune zoa, or viruses. DCs recognize virus infection either by TLRs or by effector cells (6). Secretion of chemokines occurs in coordinated waves according to the type of immune cells that need to be at- *Department of Microbiology, †Department of Neurology, and ‡Center for Transla- tracted and activated (13). One late component associated with tional Systems Biology, Mount Sinai School of Medicine, New York, NY maturation is the migration of the DCs to the secondary lymphoid Received for publication April 2, 2008. Accepted for publication September 5, 2008. organs (14), where they interact with the naive T and B cells. This The costs of publication of this article were defrayed in part by the payment of page activation of Ag-specific T cells by mature DCs is a major aspect charges. This article must therefore be hereby marked advertisement in accordance of the initiation of adaptive immunity. with 18 U.S.C. Section 1734 solely to indicate this fact. The secretion of the different cytokines and chemokines affects 1 This work was supported by Contract HHSN266200500021C and Grant U19 AI06231 from the National Institute of Allergy and Infectious Diseases. other immune cells, including immature DCs, by paracrine signal- ing. Consequently, some DCs might be exposed to both cytokines 2 A.V.B. and B.M.H. contributed equally to this work. and microbial products (11), whereas others only to inflammatory 3 Address correspondence and reprint requests to Stuart C. Sealfon, Department of Neurology and Center for Translational Systems Biology, Mount Sinai School of cytokines. Autocrine signaling is regarded as an important mech- Medicine, 1 Gustave L. Levy Place, New York, NY 10029. E-mail address: anism for virus- triggered DC maturation. Integrodifferential mod- [email protected] eling of IFN trajectories suggests that ϳ3% of IFN-␤ interacts 4 Abbreviations used in this paper: DC, dendritic cell; NDV, Newcastle disease virus; with the DCs that produce it (15). AVDC, antiviral-activated DC; MHC-I/II, MHC class I/II; Ct, crossing threshold; DiO, benzoxazolium, 3-octadecyl-2-[3-(3-octadecyl-2(3H)-benzoxazolylidene)-1-propenyl] We investigated the effects of paracrine signaling by DCs on the perchlorate; IP-10, IFN-␥-inducible protein 10; RFP, red fluorescent protein; PKR, pro- response state of DCs that are not infected by virus using NDV, tein kinase R; OAS, 2Ј-5Ј-oligoadenylate synthetase; MxA, myxovirus resistance A. which is detected primarily through the cytosolic RIG-I molecule Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 (16). To study paracrine effects, we used a Transwell system which www.jimmunol.org The Journal of Immunology 6873 is composed of two chambers separated by a membrane that allows soluble components such as cytokines and chemokines to diffuse between chambers, but prohibits direct contact be- tween the cells placed in different chambers. DCs infected with NDV and naive noninfected DCs were placed in the upper and lower chamber, respectively. The culture was left for 18 h, al- lowing the infected DCs to initiate cytokine and chemokine secretion. We found that the naive DCs exposed to the specific cytokine/chemokine secretions released by infected DCs enter a partially activated state in which they are relatively resistant to FIGURE 1. virus infection and primed to generate a more rapid and en- Experimental setup for the generation of AVDCs. hanced response to virus infection. compartment to mimic the condition during AVDC generation. We incu- Materials and Methods bated cells for 18 h at 37°C. Naive DCs in the lower compartment were Differentiation of DCs then stained for the maturation markers MHC class I (MHC-I), MHC class All human research protocols for this work have been reviewed and ap- II (MHC-II), and CD86. proved by the Institutional Review Board of the Mount Sinai School of Culture of human lung fibroblast Medicine. Monocyte-derived DCs were obtained from healthy human blood donors following a standard protocol described elsewhere (7). All Lung epithelial fibroblasts were obtained from Lonza and cultured accord- Downloaded from experiments were replicated using cells obtained from different donors. ing to the supplier’s instructions. Briefly, cells were passed when conflu- Briefly, human PBMC were isolated from buffy coats by Ficoll density ence was 70–80% using fibroblast basal medium supplemented with hu- gradient centrifugation (Histopaque; Sigma-Aldrich) at 1450 rpm and man fibroblast growth factor ␤, insulin, FBS, and gentamicin/amphotericin ϩ CD14 monocytes were immunomagnetically purified by using a B. To perform experiments in the Transwell system, 3 ϫ 105 cells were MACS CD14 isolation kit (Miltenyi Biotec).
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