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Immune Suppression Role for the Annexin A2 Heterotetramer in Human Papillomavirus Type 16: a Novel Inhibition of Langerhans Cell

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Immune Suppression Role for the Annexin A2 Heterotetramer in Human Papillomavirus Type 16: a Novel Inhibition of Langerhans Cell Inhibition of Langerhans Cell Maturation by Human Papillomavirus Type 16: A Novel Role for the Annexin A2 Heterotetramer in Immune Suppression This information is current as of October 5, 2021. Andrew W. Woodham, Adam B. Raff, Laura M. Raff, Diane M. Da Silva, Lisa Yan, Joseph G. Skeate, Michael K. Wong, Yvonne G. Lin and W. Martin Kast J Immunol 2014; 192:4748-4757; Prepublished online 9 April 2014; Downloaded from doi: 10.4049/jimmunol.1303190 http://www.jimmunol.org/content/192/10/4748 Supplementary http://www.jimmunol.org/content/suppl/2014/04/08/jimmunol.130319 http://www.jimmunol.org/ Material 0.DCSupplemental References This article cites 83 articles, 35 of which you can access for free at: http://www.jimmunol.org/content/192/10/4748.full#ref-list-1 Why The JI? Submit online. by guest on October 5, 2021 • 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 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Inhibition of Langerhans Cell Maturation by Human Papillomavirus Type 16: A Novel Role for the Annexin A2 Heterotetramer in Immune Suppression Andrew W. Woodham,*,1 Adam B. Raff,*,1,2 Laura M. Raff,* Diane M. Da Silva,†,‡ Lisa Yan,* Joseph G. Skeate,* Michael K. Wong,†,x Yvonne G. Lin,†,‡ and W. Martin Kast*,†,‡ High-risk human papillomaviruses (HPVs) are sexually transmitted viruses causally associated with several cancers. During its natural life cycle, HPV16, the most common high-risk genotype, infects the epithelial basal cells in a process facilitated through a recently identified receptor, the annexin A2 heterotetramer (A2t). During infection, HPV16 also interacts with Langerhans cells (LC), the APC of the epithelium, inducing immune suppression, which is mediated by the HPV16 L2 minor capsid protein. Despite Downloaded from the importance of these virus-immune cell interactions, the specific mechanisms of HPV16 entry into LC and HPV16-induced im- mune suppression remain undefined. An N-terminal peptide of HPV16 L2 (aa 108–126) has been shown to specifically interact with A2t. In this study, we show that incubation of human LC with this peptide blocks binding of HPV16. Inhibiting this interaction with an A2t ligand or by small interfering RNA downregulation of A2t significantly decreases HPV16 internalization into LC in an L2-dependent manner. A2t is associated with suppression of LC maturation as demonstrated through attenuated secretion of Th1- associated cytokines and decreased surface expression of MHC class II on LC exposed to A2t. Conversely, small molecule http://www.jimmunol.org/ inhibition of A2t prevents HPV16-induced suppression of LC immune function as indicated by significantly increased secretion of inflammatory cytokines and surface expression of CD86 in HPV16 treated LC pre-exposed to A2t inhibitors. These results demonstrate that HPV16 suppresses LC maturation through an interaction with A2t, revealing a novel role for this protein. The Journal of Immunology, 2014, 192: 4748–4757. ervical cancer is the second most common cancer among mechanism of infection within epithelial cells, limited studies women worldwide with .500,000 new cases reported actually focus on identifying and characterizing the HPV16 in- and .274,000 associated deaths each year (1, 2). Per- ternalization pathway in LC and how these pathways affect LC C by guest on October 5, 2021 sistent high-risk human papillomavirus (HPV) infection is caus- immune responses. ally associated with several cancers, including cervical cancer (3– HPV16 is a nonenveloped dsDNA virus whose 55-nm-diameter 5). More than half of all cervical cancer cases are associated with capsid is composed of two proteins: the L1 (late protein 1) major HPV16, the most common of the cancer-causing high-risk geno- capsid protein and the L2 (late protein 2) minor capsid protein (9), types (6). During the natural life cycle of HPV16, the virus infects each of which has unique functions during the infectious process. the basal cells of the epithelium and interacts with Langerhans Infectious HPV16 virion production depends on the differentia- cells (LC), the resident APC within the epithelia (7), which are tion of basal epithelial cells into mature keratinocytes, as the responsible for initiating immune responses against pathogens expression of late genes is contingent on host RNA factors (10). entering the epithelium (8). However, 15% of women with high- Therefore, most of the literature concerning receptors uses HPV risk HPV infections do not produce an effective immune response pseudovirions (PsV) and/or virus-like particles (VLP) to report against the virus (7), and therefore represent a critical population specific aspects of viral uptake. When expressed in vitro, the of women particularly susceptible for developing invasive cervical major capsid protein L1 self-assembles into L1 VLP, which pos- cancer. In contrast to the extensive body of research defining the sesses a 72-pentamer icosahedral structure (11–13). When L1 is *Department of Molecular Microbiology and Immunology, University of Southern hensive Cancer Center Heidelberger Award. This work was also supported by the California, Los Angeles, CA 90033; †Department of Obstetrics and Gynecology, Karl H. and Ruth M. Balz Trust. The content is solely the responsibility of the authors University of Southern California, Los Angeles, CA 90033; ‡Norris Comprehensive and does not necessarily represent the official views of the National Cancer Institute Cancer Center, University of Southern California, Los Angeles, CA 90033; and or the National Institutes of Health. xDepartment of Medicine, University of Southern California, Los Angeles, CA 90033 Address correspondence and reprint requests to Dr. W. Martin Kast, University of 1A.W.W. and A.B.R. contributed equally to this work. Southern California Norris Comprehensive Cancer Center, Harlyne Norris Research Tower, Room 7507, 1450 Biggy Street, Los Angeles, CA 90033. E-mail address: 2Current address: Harvard Combined Dermatology Program, Massachusetts General [email protected] Hospital, Boston, MA. The online version of this article contains supplemental material. Received for publication November 26, 2013. Accepted for publication March 13, 2014. Abbreviations used in this article: anxA2, annexin A2; A2t, annexin A2 heterote- tramer; A2ti, annexin A2 heterotetramer inhibitor; DC, dendritic cell; DTSSP, 3,39- This work was supported by National Institutes of Health Grants R01 CA74397 and dithiobis(sulfosuccinimidylpropionate); HPV, human papillomavirus; HSPG, heparan RC2 CA148298 to W.M.K. who holds the Walter A. Richter Cancer Research Chair. sulfate proteoglycan; LC, Langerhans cell; MHC II, MHC class II; PsV, pseudovi- A.W.W. and L.Y. are both TL1 Scholars and supported by Southern California Clin- rion; RCF, relative centrifugal force; siRNA, small interfering RNA; VLP, virus-like ical and Translational Science Institute (National Institutes of Health/National Center particle. for Research Resources/National Center for Advancing Translational Sciences) Grant TL1TR000132. A.W.W. is supported in part by National Institutes of Health Grant Ó 5P30CA014089-37 from the National Cancer Institute through the Norris Compre- Copyright 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1303190 The Journal of Immunology 4749 expressed at the same time as the minor capsid protein L2, they of A2t in LC maturation. In the present study, we expanded the assemble into L1L2 VLP with up to 72 L2 proteins per particle role for A2t as an HPV16 L2-specific receptor in epithelial cells to (12, 14). The L2 minor capsid protein plays an important role in include LC, and we additionally reveal a novel role for A2t as an efficient encapsidation of DNA within HPV16 (15, 16), allowing immune modulator of LC maturation. for the production of HPV16 L1L2 PsV that incorporate DNA within the capsid. Materials and Methods In epithelial cells, HPV16 infection is initiated upon viral capsid LC generation binding through an initial interaction between L1 and heparan Human PBMC from healthy donors were obtained by leukapheresis (48). sulfate proteoglycans (HSPG) (17), as well as other interactions LC were generated from human PBMC as previously described (49), and with a6b1/4 integrins, cyclophilin B, growth factors and growth incubated in complete media (RPMI 1640 supplemented with 10% FBS, factor receptors, and various tetraspanins (18–21). The eventual 13 penicillin/streptomycin, 13 nonessential amino acids, and 13 2-ME) uptake of HPV16 into epithelial cells has been shown to be with the addition of 1000 U/ml (∼180 ng/ml) GM-CSF, 1000 U/ml (∼200 ng/ml) IL-4, and 10 ng/ml TGF-b for 7 d. All studies were approved by clathrin-, caveolin-, cholesterol-, and dynamin-independent, which University of Southern Califonia’s Institutional Review Board, and in- points to a noncanonical and possibly novel ligand-induced in- formed consent was obtained from donors. ternalization pathway related to macropinocytosis (22). Similarly, Antibodies it was previously demonstrated that HPV16 entry into LC oc- curred via a clathrin- and caveolin-independent pathway (23), The following Abs were used in this study: mouse anti-anxA2, mouse anti- implicating a related HPV16 entry pathway into both epithelial anxA2 L chain, mouse CD86-FITC, mouse HLA-DR, DP, DQ-FITC, isotype controls (BD Biosciences, San Jose, CA); H16.V5 mouse anti- and LC. L1 (gift from Dr.
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