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Cell TLR7 Activation and Plasmacytoid Dendritic CXCL13 Secretion in Human Monocytes Via HIV-1 Single-Stra HIV-1 Single-Stranded RNA Induces CXCL13 Secretion in Human Monocytes via TLR7 Activation and Plasmacytoid Dendritic Cell −Derived Type I IFN This information is current as of October 2, 2021. Kristen W. Cohen, Anne-Sophie Dugast, Galit Alter, M. Juliana McElrath and Leonidas Stamatatos J Immunol 2015; 194:2769-2775; Prepublished online 9 February 2015; doi: 10.4049/jimmunol.1400952 Downloaded from http://www.jimmunol.org/content/194/6/2769 References This article cites 49 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/194/6/2769.full#ref-list-1 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 by guest on October 2, 2021 • 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 HIV-1 Single-Stranded RNA Induces CXCL13 Secretion in Human Monocytes via TLR7 Activation and Plasmacytoid Dendritic Cell–Derived Type I IFN Kristen W. Cohen,*,†,1 Anne-Sophie Dugast,‡ Galit Alter,‡ M. Juliana McElrath,x,1 and Leonidas Stamatatos*,†,1 Elevated levels of the chemokine CXCL13 have been observed in the plasma of chronically HIV-1–infected subjects and have been correlated with plasma viremia, which in turn has been linked to progressive dysregulation of humoral responses. In this study we sought to identify mechanisms of CXCL13 induction in response to HIV-1 infection. Plasma levels of CXCL13 in HIV-1–infected antiretroviral therapy–naive subjects correlated with viral load and were higher compared with antiretroviral therapy–treated HIV-1–infected and HIV-1–uninfected subjects. To elucidate the relationship between HIV-1 viremia and CXCL13 plasma levels, PBMCs from uninfected donors were stimulated with HIV-1 infectious virions, HIV-1 ssRNA, TLR 7 and 8 agonists, or IFN-a. Downloaded from The cellular sources of CXCL13 were determined by intracellular cytokine staining of cell populations. CXCL13 was produced by monocytes after stimulation with TLR 7 and 8 ligands or HIV-1–derived ssRNA. CXCL13 production by monocytes required TLR7 activation of plasmacytoid dendritic cells and secretion of type I IFN. IFN-a alone was sufficient to induce CXCL13 expression in human monocytes. In sum, we identified a novel mechanism of HIV-1–induced CXCL13 secretion—one caused by TLR7 induction of type I IFN by plasmacytoid dendritic cells and subsequent IFN stimulation of monocytes. Our findings are relevant in understanding how HIV-1 infection leads to immune dysregulation and provide the opportunity to develop and test http://www.jimmunol.org/ potential therapeutic interventions. The Journal of Immunology, 2015, 194: 2769–2775. characteristic immunological defect of HIV-1 infection is high-affinity Ab-secreting memory B and plasma cells are generated progressive humoral dysregulation (reviewed in Refs. 1, 2), (15, 16). Conversely, aberrant CXCL13 secretion has been impli- A which includes changes in the frequencies of specific B cell cated in the pathogenesis of many chronic inflammatory conditions, subsets (3), and results in hypergammaglobulinemia (4) and in the including various infections and autoimmune disorders associated impaired induction of de novo Ab responses to vaccination (5). Al- with dysregulated lymphoid genesis and humoral responses (17–20). though evidence exists that some of the above-mentioned defects are Elevated levels of CXCL13 have been observed in the plasma of by guest on October 2, 2021 associated with viremia (6–8), the specific mechanisms of B cell chronically HIV-1–infected subjects and have been correlated with dysregulation have yet to be elucidated. Understanding such mech- viremia (21–24). In addition, it has been shown that CXCL13 anisms may assist in the development of therapeutic interventions to plasma levels decline after suppression of virus replication by anti- restore B cell functionality in chronic HIV-1 infection. retroviral therapy (ART) (21). Furthermore, increased CXCL13 CXCL13 is a chemokine crucial for the development of secondary plasma levels were found to be associated with reduced chemokine lymphoid structures, where it is secreted by follicular dendritic cells receptor CXCR5 expression on B cells, with alterations in the che- (DCs) in response to lymphotoxin receptor activation (9, 10). CXCL13 motactic potential of B cells, and correlated inversely with the fre- is chemotactic for cells expressing the receptor CXCR5 (9, 11), quency of circulating Tfh cells during chronic HIV-1 infection (22, including mature B cells and T follicular helper (Tfh) cells (12–14), 24). It appears, therefore, that CXCL13 is a factor linked with the and is expressed at high levels in the B cell follicles of lymphoid dysregulation of B cell function during HIV-1 infection. However, it organs (9). Importantly, CXCL13 facilitates the comigration of is unclear how HIV-1 infection leads to increased plasma CXCL13 B cells and Tfh cells into B cell follicles and germinal centers, where concentrations and how changes in CXCL13 plasma concentration are linked with B cell dysregulation during HIV-1 infection. Al- though increased transcriptional expression of CXCL13 is detected *Seattle Biomedical Research Institute, Seattle, WA 98109; †Department of Global Health, University of Washington, Seattle, WA 98195; ‡Ragon Institute of MGH, in B cells from HIV-1–infected subjects, secretion of CXCL13 by MIT and Harvard, Cambridge, MA 02139; and xDepartment of Medicine, University those B cells is detectable only at low levels and only after stimu- of Washington, Seattle, WA 98195 lation for 6 d with CD40 ligation, CpG, IL-2, and IL-10 (22). 1 Current address: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Therefore, the reported increases in CXCL13 concentrations during Research Center, Seattle, WA. HIV-1 infection are likely not due to increases in CXCL13 pro- Received for publication April 14, 2014. Accepted for publication January 8, 2015. duction by B cells. In contrast, in lymph node biopsies from these This work was supported by National Institutes of Health Grants AI081625 (to L.S.) same subjects, the majority of CXCL13 was found in macrophages and AI080289 (to M.J.M.). and immature DCs (22). Whether these two cell types secrete Address correspondence and reprint requests to Dr. Leonidas Stamatatos at the cur- rent address: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, CXCL13 in the periphery is unknown. It is also not understood Room E5-420, Seattle, WA 98109. E-mail address: [email protected] whether CXCL13 expression by macrophages and immature DCs is Abbreviations used in this article: ART, antiretroviral therapy; AZT, azidothymidine; the direct result of their infection by HIV-1 or is due to a bystander DC, dendritic cell; mDC, myeloid DC; pDC, plasmacytoid DC; Tfh, T follicular effect of immune activation that takes place during HIV-1 infection. helper; TLR7/8, TLRs 7 and 8. In this regard, it is known that HIV-1–derived RNA triggers Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 cytokine secretion directly through activation of TLRs 7 and 8 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400952 2770 HIV-1 INDUCTION OF CXCL13 IN MONOCYTES (TLR7/8) (25, 26), which are predominantly expressed by APCs mAbs against CD19, CD3, CD14, CD11c, and CD123 (BD Biosciences) such as monocytes, monocyte-derived DCs, and myeloid cells (27). and analyzed using an LSR II flow cytometer. In addition, monocytes, macrophages, and monocyte-derived DCs In vitro stimulation of PBMCs with TLR ligands have been identified as inducible producers of CXCL13 by TLR2 A total of 2 million freshly isolated PBMCs or 2 3 105 monocytes incubated and TLR4 activation (17, 20, 28–30). TLRs 2, 4, 7, and 8 share over- with or without 25,000 purified pDCs were cultured in 1 ml complete media lapping signaling pathways and downstream transcription factors. and treated for 1–4 d with the TLR7/8 agonist R848 (Invivogen) at 1 mg/ml. Therefore, increases in CXCL13 plasma concentrations during Increasing concentrations of HIV-1 long terminal repeat–derived GU-rich HIV-1 infection could be due to secretion of this chemokine by any ssRNA40/LyoVec (59-GCCCGUCUGUUGUGUGACUC-39) and negative (or all) of these cells through TLR-activated pathways. control RNA, in which U nucleotides were replaced with adenosine, ssRNA41/LyoVec (59-GCCCGACAGAAGAGAGACAC-39) (26) (Inviv- In this article, we report that CXCL13 is secreted by monocytes in ogen), and recombinant human IFN-a2A (PBL IFN) were added to cells. response to stimulation with HIV-1 virions, HIV-1–derived ssRNA, The soluble IFNR B18R (Affymetrix) was added (at 0.1 mg/ml) to cells and the TLR7/8 ligand R848. Of interest, maximal CXCL13 directly preceding stimulation with the above TLR7/8 agonists to neutralize m production required plasmacytoid DC (pDC) secretion of IFN-I. type I IFN in the supernatant. For time course experiments, 500 l super- natant was removed and replaced with fresh media at 24-h intervals. Therefore, our study reveals a novel mechanism of CXCL13 in- Concentrations of CXCL13 and IFN-a in culture supernatants were deter- duction in human monocytes via the TLR7 stimulation of pDCs mined by ELISA according to the manufacturers’ instructions (IFN-a kit and secretion of IFN-I and subsequent IFN-induced production of from PBL Biomedical Laboratories; CXCL13 kits from R&D systems).
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