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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 Kast^2,*,,

^* Department of Molecular Microbiology & Immunology, Systems Biology and Disease Program, Department of Obstetrics & Gynecology, and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033

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 responsible 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 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 proinflammatory 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 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 with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These studies were supported by National Institutes of Health Grant R01 CA 74397 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 T32 GM0607587 (to A.B.R.). W.M.K. holds the Walter A. Richter Cancer Research Chair.

² Address correspondence and reprint requests to Dr. W. Martin Kast, Norris Comprehensive Cancer Center, University of Southern California, 1450 Biggy Street, NRT 7507, Los Angeles, CA 90033. E-mail address: mkast{at}usc.edu

³ Abbreviations used in this paper: HPV, human papillomavirus; LC, Langerhans cell; LN, lymph node; SLC, secondary lymphoid tissue chemokine; cVLP, chimeric virus-like particle; VLP, virus-like particle; DC, dendritic cell; IP-10, IFN-inducible protein 10.

This article has been cited by other articles:

				L. M. Fahey, A. B. Raff, D. M. Da Silva, and W. M. Kast A Major Role for the Minor Capsid Protein of Human Papillomavirus Type 16 in Immune Escape J. Immunol., November 15, 2009; 183(10): 6151 - 6156. [Abstract] [Full Text] [PDF]