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Identification of RNA Sequence Motifs Stimulating Sequence-Specific TLR8-Dependent Immune Responses¹

Alexandra Forsbach^*, Jean-Guy Nemorin, Carmen Montino^*, Christian Müller^*, Ulrike Samulowitz^*, Alain P. Vicari, Marion Jurk^*, George K. Mutwiri, Arthur M. Krieg, Grayson B. Lipford and Jörg Vollmer^2,*

^* Coley Pharmaceutical GmbH, Düsseldorf, Germany; Coley Pharmaceutical Ltd., Ottawa, Ontario, Canada; Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; and Coley Pharmaceutical Group, Inc., Wellesley, MA 02481

The TLRs 7, 8, and 9 stimulate innate immune responses upon recognizing pathogen nucleic acids. U-rich RNA sequences were recently discovered that stimulate human TLR7/8-mediated or murine TLR7-mediated immune effects. In this study we identified single-stranded RNA sequences containing defined sequence motifs that either preferentially activate human TLR8-mediated as opposed to TLR7- or TLR7/8-mediated immune responses. The identified TLR8 RNA motifs signal via TLR8 and fail to induce IFN- from TLR7-expressing plasmacytoid dendritic cells but induce the secretion of Th1-like and proinflammatory cytokines from TLR8-expressing immune cells such as monocytes or myeloid dendritic cells. In contrast, RNA sequences containing the TLR7/8 motif signal via TLR7 and TLR8 and stimulate cytokine secretion from both TLR7- and TLR8-positive immunocytes. The TLR8-specific RNA sequences are able to trigger cytokine responses from human and bovine but not from mouse, rat, and porcine immune cells, suggesting that these species lack the capability to respond properly to TLR8 RNA ligands. In summary, we describe two classes of single-stranded TLR7/8 and TLR8 RNA agonists with diverse target cell and species specificities and immune response profiles.

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 This study was supported by National Institute of Allergy and Infectious Diseases Contract HHSSN266200400044C.

² Address correspondence and reprint requests to Dr. Jörg Vollmer, Coley Pharmaceutical GmbH, Merowingerplatz 1a, 40225 Düsseldorf, Germany. E-mail address: jvollmer{at}coleypharma.com

³ Abbreviations used in this paper: ORN, oligoribonucleotide; BDCA, blood DC Ag; DC, dendritic cell; DOTAP, 1,3-dioleoyloxy-3-(trimethylammonium)propane; ECD, ectodomain; HEK, human embryonic kidney; IP-10, IFN--inducible protein-10; LRR, leucine rich repeat; mDC, myeloid DC; ODN, oligodeoxynucleotide; PDC, plasmacytoid DC; poly(rI:rC), polyriboinosinic:polyribocytidylic acid; SN, supernatant.