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2919.Full.Pdf Reversal of Human Papillomavirus-Specific T Cell Immune Suppression through TLR Agonist Treatment of Langerhans Cells Exposed to Human Papillomavirus Type 16 This information is current as of September 24, 2021. Laura M. Fahey, Adam B. Raff, Diane M. Da Silva and W. Martin Kast J Immunol 2009; 182:2919-2928; ; doi: 10.4049/jimmunol.0803645 http://www.jimmunol.org/content/182/5/2919 Downloaded from References This article cites 50 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/182/5/2919.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 • 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 © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Reversal of Human Papillomavirus-Specific T Cell Immune Suppression through TLR Agonist Treatment of Langerhans Cells Exposed to Human Papillomavirus Type 161 Laura M. Fahey,* Adam B. Raff,† Diane M. Da Silva,‡§ and W. Martin Kast2*‡§ Human papillomavirus (HPV) type 16 infects the epithelial layer of cervical mucosa and is causally associated with the generation of cervical cancer. Langerhans cells (LC) are the resident APCs at the site of infection and therefore are re- sponsible for initiating an immune response against HPV16. On the contrary, LC exposed to HPV16 do not induce a specific T cell immune response, which leads to the immune evasion of HPV16. Demonstrating that TLR7 and TLR8 are expressed on human LC, we hypothesized that imidazoquinolines would activate LC exposed to HPV16, leading to the induction of an HPV16-specific cell-mediated immune response. Surprisingly, both phenotypic and functional hallmarks of activation are not Downloaded from observed when LC are exposed to HPV16 virus-like particles and treated with imiquimod (TLR7 agonist). However, we found that LC are activated by 3M-002 (TLR8 agonist) and resiquimod (TLR8/7 agonist). LC exposed to HPV16 virus-like particles and subsequently treated with 3M-002 or resiquimod highly up-regulate surface activation markers, secrete proin- flammatory cytokines and chemokines, induce CCL21-directed migration, and initiate an HPV16-specific CD8؉ T cell response. These data strongly indicate that 3M-002 and resiquimod are promising therapeutics for treatment of HPV infections and HPV-induced cervical lesions. The Journal of Immunology, 2009, 182: 2919–2928. http://www.jimmunol.org/ igh-risk human papillomaviruses (HPV)3 are causally rate and lack of an effective immune response indicates that HPV linked to the generation of cervical cancer (1, 2). Cer- is escaping immune detection (12). Thus, therapeutic treatments H vical cancer is the second most common cancer among are necessary to treat existing high-risk HPV infections. women worldwide, killing approximately one-quarter of a million High-risk HPV infects the epidermal layer of the mucosa where women each year (3). Merck has developed the first prophylatic Langerhans cells (LC) are the primary APC. The principal functions HPV vaccine, Gardasil. It has been demonstrated in phase III clin- of APC are recognition, internalization, processing, transport, and pre- ical trials to be 100% effective in preventing high-grade cervical sentation of Ags to unprimed T cells in the lymph node (LN) (13–17). lesions associated with HPV16 and HPV18 (4, 5). Despite the Since LC are the only APC that HPV will come into contact with by guest on September 24, 2021 success of Gardasil, it has been predicted that it will take decades during an infection, they are responsible for initiating a cell-mediated to detect a quantifiable effect on cervical cancer rates in the pop- immune response against HPV. However, we previously demon- ulation (6, 7). Additionally, Gardasil will not aid in treating the strated that human LC do not initiate a specific anti-HPV16 CD8ϩ T hundreds of millions of women that are currently infected with cell response after exposure to chimeric HPV16L1L2-E7 virus-like high-risk HPV. The majority of women infected with HPV clear particles (HPV16 cVLP) (18, 19). Additionally, LC exposed to the virus; however, the average time for clearance is close to 1 year HPV16L1L2 virus-like particles (HPV16 VLP) appear to have a (8, 9). Conversely, ϳ15% of women that have high-risk HPV in- tolerizing phenotype, cross-presenting HPV peptides on MHC mole- fections cannot initiate an effective immune response against HPV cules in the absence of surface markers important for T cell costimu- and persistence of high-risk HPV infection is a major risk factor in the development of cervical cancer (10, 11). The slow clearance lation and migration, including CD80, CD86, and CCR7, and without secretion of proinflammatory cytokines. The molecular mechanism mediating this immune escape process is the activation of PI3K in LC *Department of Molecular Microbiology & Immunology, †Systems Biology and Dis- (18–20). As a result, HPV can evade the immune system, leading to ease Program, ‡Department of Obstetrics & Gynecology, and §Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033 the delay or absence of viral clearance. Received for publication October 31, 2008. Accepted for publication January 3, 2009. As we demonstrate here, LC express TLR7 and TLR8; thus, a potential therapy of HPV16-induced lesions would be to ac- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance tivate HPV16-infected LC using synthetic imidazoquinolines with 18 U.S.C. Section 1734 solely to indicate this fact. (imiquimod, resiquimod, 3M-002, and 3M-031). Imidazoquino- 1 These studies were supported by National Institutes of Health Grant R01 CA 74397 lines are TLR7 and/or TLR8 agonists and therefore are potent and a Whittier Foundation grant (to W.M.K.), a National Institutes of Health Training Grant T32 AI07078 (to L.M.F.), and a National Institutes of Health Training Grant innate immune modulators (Table I and Ref. 21). TLR7 and T32 GM0607587 (to A.B.R.). W.M.K. holds the Walter A. Richter Cancer Research TLR8 are localized to endosomal membranes and naturally rec- Chair. ognize ssRNA (21, 22). Once TLR7 and/or TLR8 are engaged, 2 Address correspondence and reprint requests to Dr. W. Martin Kast, Norris Com- NF-␬B and other transcription factors are activated, leading to prehensive Cancer Center, University of Southern California, 1450 Biggy Street, NRT 7507, Los Angeles, CA 90033. E-mail address: [email protected] the transcription of immune response-related genes, including 3 Abbreviations used in this paper: HPV, human papillomavirus; LC, Langerhans cell; cytokine, chemokine, costimulatory marker, and adhesion mol- LN, lymph node; SLC, secondary lymphoid tissue chemokine; cVLP, chimeric virus-like ecule genes (21, 23, 24). Moreover, imidazoquinolines demon- particle; VLP, virus-like particle; DC, dendritic cell; IP-10, IFN-inducible protein 10. strate antiviral and antitumor activity through cytokines and che- Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 mokines, such as TNF-␣, IL-6, IL-8, IL-12, and IFN-inducible www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803645 2920 EFFECTS OF TLR8 AGONISTS ON LC Table I. Synthetic imidazoquinolines and the respective receptor(s) they previously described (30, 31). Western blot analysis confirmed the pres- bind and act through ence of L1, L2, and, in the case of chimeric particles, the E7 protein. To test for intact particles, VLP were subjected to an ELISA using Abs that rec- ognize conformationally dependent L1 surface epitopes or linear epitopes, Imidazoquinoline Agonist Receptor(s) and transmission electron microscopy. An E-toxate kit (Sigma-Aldrich) 3M-006 Inactive analog (TLR7/8) was used to quantitate endotoxin and levels in the preparations were found Ͻ 3M-002 TLR8 to be l 0.06 endotoxin units/ml. This level as well as baculovirus DNA Imiquimod TLR7 used in the VLP production procedure do not activate APC (18). Resiquimod TLR8/7 Imidazoquinoline activation assay 3M-031 TLR7/8 DC and LC were harvested and washed twice with PBS. DC were left untreated or treated with 30 ␮M 3M-006, 5 ␮M 3M-002, 30 ␮M imi- protein 10 (IP-10), produced by dendritic cells (DC) and macro- quimod, 30 ␮M resiquimod, 5 ␮M 3M-031, or with 10 ␮g LPS (Esche- phages (21, 25–29). richia coli 026:B6; Sigma-Aldrich). The cells were incubated for1hat 37°C, mixed occasionally, and finally placed at 37°C for 24 h in complete Confirming that TLR7 and TLR8 are expressed on LC, we hy- medium containing 1000 U/ml rGM-CSF. LC were left untreated or ex- pothesized that synthetic imidazoquinolines would activate LC posed to HPV16 VLP at a concentration of 10 ␮g/106 cells. The cells were previously exposed to HPV16, leading to the induction of an incubated for1hat37°C, mixed occasionally, and placed at 37°C for 24 h HPV16-specific immune response. Our results indicate that select in complete medium containing 1000 U/ml rGM-CSF. Next, the cells were left untreated or treated with 30 ␮M 3M-006, 5 ␮M 3M-002, 30 ␮M imidazoquinolines, TLR8 dominant agonists, are promising ther- imiquimod, 30 ␮M resiquimod, 5 ␮M 3M-031, or 10 ␮g of LPS and apeutic drugs that could potentially be used as a treatment for HPV incubated for an additional 24 h at 37°C.
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