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S1PR4 Signaling Attenuates ILT 7 Internalization to Limit IFN- Α Production by Human Plasmacytoid Dendritic Cells

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S1PR4 Signaling Attenuates ILT 7 Internalization to Limit IFN- Α Production by Human Plasmacytoid Dendritic Cells S1PR4 Signaling Attenuates ILT 7 Internalization To Limit IFN- α Production by Human Plasmacytoid Dendritic Cells This information is current as Christina Dillmann, Christian Ringel, Julia Ringleb, Javier of September 24, 2021. Mora, Catherine Olesch, Annika F. Fink, Edward Roberts, Bernhard Brüne and Andreas Weigert J Immunol published online 18 January 2016 http://www.jimmunol.org/content/early/2016/01/15/jimmun ol.1403168 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/01/15/jimmunol.140316 Material 8.DCSupplemental 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 24, 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 18, 2016, doi:10.4049/jimmunol.1403168 The Journal of Immunology S1PR4 Signaling Attenuates ILT 7 Internalization To Limit IFN-a Production by Human Plasmacytoid Dendritic Cells Christina Dillmann,* Christian Ringel,* Julia Ringleb,* Javier Mora,* Catherine Olesch,* Annika F. Fink,* Edward Roberts,† Bernhard Brune,*€ and Andreas Weigert* Plasmacytoid dendritic cells (pDCs) produce large amounts of type I IFN in response to TLR7/9 ligands. This conveys antiviral effects, activates other immune cells (NK cells, conventional DCs, B, and T cells), and causes the induction and expansion of a strong inflammatory response. pDCs are key players in various type I IFN–driven autoimmune diseases such as systemic lupus erythematosus or psoriasis, but pDCs are also involved in (anti-)tumor immunity. The sphingolipid sphingosine-1-phosphate (S1P) signals through five G-protein–coupled receptors (S1PR1–5) to regulate, among other activities, immune cell migration and activation. The present study shows that S1P stimulation of human, primary pDCs substantially decreases IFN-a produc- tion after TLR7/9 activation with different types of CpG oligodeoxynucleotides or tick-borne encephalitis vaccine, which Downloaded from occurred in an S1PR4-dependent manner. Mechanistically, S1PR4 activation preserves the surface expression of the human pDC-specific inhibitory receptor Ig-like transcript 7. We provide novel information that Ig-like transcript 7 is rapidly internalized upon receptor-mediated endocytosis of TLR7/9 ligands to allow high IFN-a production. This is antagonized by S1PR4 signaling, thus decreasing TLR-induced IFN-a secretion. At a functional level, attenuated IFN-a production failed to alter Ag-driven T cell proliferation in pDC-dependent T cell activation assays, but shifted cytokine production of T cells from a Th1 (IFN-g) to a regulatory (IL-10) profile. In conclusion, S1PR4 agonists block human pDC activation and may therefore be a promising http://www.jimmunol.org/ tool to restrict pathogenic IFN-a production. The Journal of Immunology, 2016, 196: 000–000. lasmacytoid dendritic cells (pDCs) are a rare DC sub- the transcription factor IFN regulatory factor 7 (IRF7) (3). TLR7 population, characterized by their potent ability to pro- and -9 sense viral ssRNA and unmethylated CpG oligodeoxy- P duce large amounts of type I IFN (IFN-a/b; IFN-I), a nucleotides (ODNs), respectively, and are located within endo- plasma cell-like morphology, and a unique set of cell-surface somes. The subcellular localization of TLR7/9 prevents the host markers. IFN-a plays a crucial role in antiviral immunity by to respond to self-DNA, which might induce autoreactive im- augmenting the expression of a broad repertoire of antiviral mune responses. The uptake of physiological TLR7/9 ligands by guest on September 24, 2021 molecules that dampen viral spread and promote apoptosis of and their shuttling to the endosomal compartment is a con- infected cells (reviewed in Ref. 1). Furthermore, IFN-a was trolled, receptor-mediated process. However, detailed mecha- shown to inhibit the growth of cells undergoing malignant nisms of TLR7/9 ligand uptake are currently unclear and require transformation (reviewed in Ref. 2). In pDCs, IFN-a is produced further investigation (4). mainly via the TLR7/9–MyD88 pathway and the rapid produc- Controlling pDC activation is indispensable to avoid an tion of high levels IFN-a is due to the constitutive expression of overshooting immune response that can harm the host. There- fore, pDCs express a set of regulatory surface receptors that *Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, regulate IFN-a production. Among these, Ig-like transcript 7 60590 Frankfurt, Germany; and †Department of Chemistry, The Scripps Research (ILT7), a surface marker exclusively expressed on human pDCs, Institute, La Jolla, CA 92037 was shown to associate with the adapter protein FcεRIg. Acti- ORCID: 0000-0002-7276-3838 (J.M.). vation of this receptor complex causes ITAM-mediated signal- Received for publication December 19, 2014. Accepted for publication December 9, ing to restrict IFN-a production (5–7). The only known ligand 2015. for ILT7 is bone marrow stromal Ag 2 (BST2), which is This work is supported by the Else Kro¨ner-Fresenius Foundation Research Training expressedonimmunecellssuchaspDCs,butalsooncancer Group Translational Research Innovation–Pharma, the Sander Foundation (2013.036. 01), the Deutsche Krebshilfe (110637), and by the Deutsche Forschungsgemeinschaft cells, including melanoma and breast cancer (8). The current (SFB 1039 TP B04 and SFB 1039 TP B06). model of ILT7/BST2 interaction suggests that BST2 expression Address correspondence and reprint requests to Dr. Andreas Weigert, Faculty of is upregulated in an inflammatory environment to interact with Medicine, Institute of Biochemistry I–Pathobiochemistry, Goethe-University ILT7, serving as a negative-feedback loop to prevent an un- Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail address: [email protected] controlled and overshooting IFN-a response. In contrast, con- The online version of this article contains supplemental material. stitutive expression of BST2 by various cancer types inhibits IFN-a production of tumor-infiltrating pDCs. As IFN-a has Abbreviations used in this article: BST2, bone marrow stromal Ag 2; CBA, cyto- metric bead array; cDC, conventional DC; DC, dendritic cell; FSME, tick-borne antiangiogenic and proapoptotic effects on cancer cells, this encephalitis vaccine; GrB, granzyme B; IFN-I, type I IFN; IMQ, imiquimod; mechanism allows tumor-associated immunosuppression. How- IRF7, IFN regulatory factor 7; ISG, IFN-I–stimulated gene; LPI, Lyn peptide inhib- itor; MHC I, MHC class I; MHC II, MHC class II; ODN, oligodeoxynucleotide; pDC, ever, leukemic pDCs tend to downregulate ILT7 although the plasmacytoid dendritic cell; qPCR, quantitative PCR; ROCK, Rho-associated pro- underlying reason is unclear (9). pDCs were shown to infiltrate hu- tein kinase; siRNA, small interfering RNA; S1P, sphingosine-1-phosphate; S1PR, man solid tumors without secreting adequate levels of IFN-a after sphingosine-1-phosphate receptor; Treg, regulatory T cell; TTX, tetanus toxoid. TLR9 activation (10). Tumors orchestrate an immunosuppressive Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 microenvironment, which is characterized by specific mediators www.jimmunol.org/cgi/doi/10.4049/jimmunol.1403168 2 S1P INHIBITS IFN-a FROM pDCs (e.g., sphingosine-1-phosphate [S1P], PGE2, IL-10, vascular en- RNA isolation and quantitative RT-PCR dothelial growth factor, and TGF-b), released from tumor- RNA from PBMCs was isolated using peqGold RNA Pure (Peqlab associated immune or cancer cells, favoring regulatory immune Biotechnologie, Erlangen, Germany) followed by cDNA transcription € cell phenotypes (reviewed in Ref. 11). Furthermore, pDCs, like all with the iScript cDNA synthesis kit (Bio-Rad, Munchen, Germany). pDC RNA (#1 3 106 cells/sample) was isolated using the RNeasy Micro kit DCs, are able to present Ags to T cells and therefore induce, (Qiagen, Hilden, Germany) and quantitated using the Bioanalyzer depending on the microenvironment, variable adaptive immune (Agilent Technologies, Bo¨blingen, Germany) followed by transcription responses. There is evidence that pDCs promote regulatory T cell with sensiscript RT kits (Qiagen). Real-time quantitative PCR (qPCR) (Treg) expansion within the tumor by presentation of self-Ags to was performed using the MyIQ real-time PCR system (Bio-Rad) and naive T cells. However, other studies show that fully activated Absolute Blue qPCR SYBR Green fluorescein mix (Thermo Scientific, Karlsruhe, Germany). Primers against all S1P receptors (S1PR1–5), IFN-a2, pDCs can have a cytotoxic, tumoricidal function (12). and IRF7 were from Qiagen. Additional primers (Biomers, Ulm, Germany) S1P is a bioactive sphingolipid mediator that is produced by were: Mx1 sense, 59-CACCGTGACACTGGGATTC-39 and antisense, 59- various (immune)
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