title: Plasmacytoid dendritic cell-derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists.
abstract: There is a high demand for the development of adjuvants that induce cytotoxic T lymphocytes, which are crucial for the elimination of intracellular pathogens and tumor cells. Toll-like receptor (TLR) agonists are prime candidates to fulfill this role because they induce innate immune activation and promote adaptive immune responses. The successful application of the TLR7 agonist R837 for treatment of basal cell carcinoma shows the potential for exploiting this pathway in tumor immunotherapy. Imidazoquinolines like R837 and stimulatory ssRNA oligonucleotides both trigger TLR7-mediated immune activation, but little is known about their comparative ability to promote immunity induction. We investigated differences in innate immune activation and adjuvant activity between the imidazoquinoline R848 and the ssRNA TLR7 agonist polyUs21. In contrast to R848, polyUs21 induced detectable levels of intracellular interferon-alpha (IFN-alpha) in plasmacytoid dendritic cells (PDCs). In immunization studies, only polyUs21 led to robust priming of type 1 T helper cells and cytotoxic T lymphocytes, and it was more efficient in inducing antitumor immunity than R848. Notably, exogenous IFN-alpha augmented the adjuvant activity of R848, whereas depletion of PDC abrogated the adjuvanticity of polyUs21. This study, therefore, identifies sufficient IFN-alpha production by PDC as an important determinant of vaccine efficacy.
authors.affiliation: King's College London, Peter Gorer Department of Immunobiology, Guy's Hospital, London, United Kingdom.
authors.forename: Deepa
authors.initials: D
authors.lastname: Rajagopal
authors.forename: Carine
authors.initials: C
authors.lastname: Paturel
authors.forename: Yannis
authors.initials: Y
authors.lastname: Morel
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Diebold
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000634:Aminoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019496:Cancer Vaccines / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D000077271:Imiquimod; D007370:Interferon Type I / Q000378:metabolism / Q000502:physiology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011804:Quinolines / Q000494:pharmacology; D012313:RNA / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D007093:Imidazoles; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D011804:Quinolines; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D053633:Receptor, Interferon alpha-beta; D012313:RNA; D000077271:Imiquimod; C402365:resiquimod